Hsp90-targeted inflammation and infection imaging and therapy

ABSTRACT

The present invention provides new methods for inflammation and infection imaging and related medical applications thereof. In some embodiments, the present invention provides a method for the diagnosis of inflammation and/or infection. In some embodiments, the present invention provides a method for the treatment or prevention of inflammation and/or infection. In some embodiments, the present invention provides methods for monitoring the effect of inflammation and/or infection treatment, and/or methods for monitoring an inflammation and/or infection treatment regimen. In some embodiments, the present invention provides a method for selecting subjects for an inflammation and/or infection treatment. In some embodiments, the present invention provides a method for determining the dosage of a drug for the treatment of inflammation and/or infection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application62/051,590 filed on Sep. 17, 2014, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Inflammation is part of the complex biological response of vasculartissues to harmful stimuli, such as pathogens, damaged cells, orirritants. The classical signs of acute inflammation are pain, heat,redness, swelling, and loss of function. Inflammation is a protectiveattempt by the organism to remove the injurious stimuli and to initiatethe healing process. In an inflammatory response, cytokines andchemokines are released from various cell types, which increases bloodvessel permeability, upregulates endothelial receptors, and increasesegress of various cells of the innate and adaptive immune system toenter surrounding tissue. In autoimmune diseases, the immune systemtriggers an inflammatory response when there are no harmful stimuli,thus causing damages to normal tissues.

Inflammation can be a localized reaction of live tissue due to aninjury, which may be caused by various endogenous and exogenous factors.The exogenous factors include physical, chemical, and biologicalfactors. The endogenous factors include inflammatory mediators,antigens, and antibodies. Endogenous factors often develop under theinfluence of an exogenous damage. An inflammatory reaction is oftenfollowed by an altered structure and penetrability of the cellularmembrane. Endogenous factors, namely, mediators, antigens, and autogensdefine the nature and type of an inflammatory reaction, especially itscourse in the zone of injury. In the case where tissue damage is limitedto the creation of mediators, an acute form of inflammation develops. Ifimmunologic reactions are also involved in the process, through theinteraction of antigens, antibodies, and autoantigens, a long-terminflammatory process will develop. Various exogenous agents, forexample, infection, injury, radiation, also further the course ofinflammatory process on a molecular level by damaging cellular membraneswhich initiate biochemical reactions.

Infection is the invasion of a host organism's body tissues bydisease-causing agents, their multiplication, and the reaction of hosttissues to these organisms and the toxins they produce. Thedisease-causing agents can be infectious agents such as viruses,viroids, and prions, microorganisms such as bacteria, nematodes such asroundworms and pinworms, arthropods such as ticks, mites, fleas, andlice, fungi such as ringworm, or macroparasites such as tapeworms.Symptoms of an infection can be signs affecting the whole body, such asfatigue, loss of appetite, weight loss, fevers, night sweats, chills,aches and pains, or signs specific to individual body parts, such asskin rashes, coughing, or a runny nose. Hosts can fight infections usingtheir immune system. Mammalian hosts react to infections with an innateresponse, often involving inflammation, followed by an adaptiveresponse. Infections can cause host tissue damage. In certain cases, thehost's protective immune mechanisms are compromised, and the organisminflicts damage on the host. In some cases, microorganisms cause tissuedamage by releasing a variety of toxins or destructive enzymes.

Targeted imaging for targeted therapy—using radiolabeled forms oftargeted therapeutic agents for PET imaging—is much advocated for thefuture of medical imaging & drug development, by the National CancerInstitute and others. (National Cancer Institute, U.S. NationalInstitutes of Health. A workshop regarding what in-vivo molecularimaging probes are needed to support future translational studies incancer therapeutics. Paper presented at: Strategies for Imaging PriorityTargets, 2002; Frankfurt, Germany; Weber W A et al. Nat Clin PractOncol. 2008; 5(1):44-54; Workman P et al. J Natl Cancer Inst. 2006;98(9):580-598; Workman P et al. Ann N Y Acad Sci. 2007; 1113:202-216).The unique potential of PET microdose studies in development of drugs astherapeutic and/or diagnostic imaging agents is recognized by the US FDAand others. A review of published PET micro-dosing studies is providedby Wagner et al (Wagner C C et al. Curr Opin Drug Discov Devel. 2008January; 11(1):104-10).

Various agents for infection and/or inflammation imaging are currentlyin clinical use (Petruzzi et al. Semin. Nucl. Med. 2009; 39(2):115-123). However, more imaging agents will provide additional optionsfor imaging, diagnostics, and treatment of infection and/orinflammation.

SUMMARY OF THE INVENTION

The present invention, among other things, encompasses the recognitionthat Hsp90 plays a role in mediating inflammation and/or infection (sece.g., “The psoriasis-associated D10N variant of the adaptor Act1 withimpaired regulation by the molecular chaperone hsp90,” 2013; Nat.Immunol. 14(1):72-81), and that further understanding the role of Hsp90in inflammation and infection can be valuable in the diagnosis andtreatment of inflammation and/or infection. In some embodiments, thepresent invention solves certain problems associated with conventionalimaging of a tissue affected by an inflammation and/or infection. Insome embodiments, the present invention provides methods fornon-invasive imaging of inflammation and/or infection. In certainembodiments, the present invention provides novel methods formonitoring, diagnosis, and treatment of an inflammation and/orinfection. In some embodiments, provided methods comprise imaging aninflammation and/or infection using labeled compounds that bind toHsp90, and/or labeled compounds having the structure of any of formula Ito IX. In some embodiments, provided methods comprise imaging aninflammation and/or infection using labeled compounds that bind toHsp90, and/or labeled compounds having the structure of formula I. Insome embodiments, the invention provides a method for detecting andtreating an inflammation and/or infection, wherein higher uptake of theHsp90-targeted imaging agent indicates more likelihood for the subjectto benefit from Hsp90 inhibitor therapy.

In some embodiments, the present invention provides a method of imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of: (a) administering to the subject alabeled compound that binds to Hsp90; and (b) imaging the tissue bydetecting the labeled compound in the subject.

In some embodiments, the present invention provides a method for imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of: (a) administering to the subject alabeled compound of any of formula I to IX as described herein; and (b)imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method for imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

(a) administering to the subject a labeled compound of formula I:

or its pharmaceutically acceptable salt thereof, wherein each of Y, R,X₁, X₂, X₃, and X₄ is a defined herein; wherein each hydrogen isoptionally and independently substituted with a group that can bedetected by a medical imaging technique, and/or at least one atom in thecompound is optionally enriched in an isotope that can be detected by amedical imaging technique; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method for thediagnosis of a tissue affected by an inflammation and/or infection,comprising steps of:

(a) administering a compound of any of formula I to IX to a subject inneed thereof; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method for thetreatment of a tissue affected by, or prevention of a tissue from, aninflammation and/or infection, comprising steps of:

(a) administering a compound of any of formula I to IX to a subject inneed thereof; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method formonitoring the effect of an inflammation and/or infection treatment in asubject in need thereof; comprising steps of:

(a) administering a labeled compound of any of formula I to IX to thesubject who is scheduled for the inflammation and/or infectiontreatment, currently undergoing the inflammation and/or infectiontreatment, or has completed or discontinued the inflammation and/orinfection treatment;

(b) imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound; and

(c) recommending to the subject an appropriate avoidance, continuation,modification, or termination in the inflammation and/or infectiontreatment.

In some embodiments, the present invention provides a method formonitoring an inflammation and/or infection treatment regimen,comprising steps of:

(a) administering a labeled compound of any of formula I to IX to asubject under the inflammation and/or infection treatment regimen;

(b) imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound in the subject;

(c) analyzing the images from step (b); and

(d) maintaining, modifying or discontinuing the inflammation and/orinfection treatment regimen.

In some embodiments, the present invention provides a method forselecting subjects for an inflammation and/or infection treatment,comprising steps of:

(a) administering a labeled compound of any of formula I to IX to asubject;

(b) imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound in the subject;

(c) analyzing the images from step (b); and

(d) including or excluding the subject for the treatment.

In some embodiments, the present invention provides a method forselecting subjects for an inflammation and/or infection treatment,comprising steps of:

(a) administering to a subject a labeled compound that binds tostress-specific Hsp90; and

(b) imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound in the subject;

wherein increased uptake of the labeled compound indicates morelikelihood for the subject to benefit from the treatment.

In some embodiments, the present invention provides a method fordetermining the dosage of a drug for the treatment of an inflammationand/or infection, comprising steps of:

(a) administering a labeled compound of any of formula I to IX to asubject;

(b) imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound in the subject;

(c) analyzing the images from step (b); and

(d) administering to the subject a suitable amount of the drug.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: I-124 PUH71 PET-CT of a chronic pulmonary infiltrate in a 59year old woman with ovarian cancer. Shown are I-124 PUH71 PET-CT imagesof a single transaxial plane through the chest, showing distinctaccumulation of I-124 PUH71 in an inflammatory pulmonary infiltrate(arrows) in the apex of the patient's left lung. PET-CT imaging wasperformed 24 hours after intravenous injection of 9.3 mCi 1-124 PUH71.Shown are I-124 PUH71 PET images with and without attenuation correction(top right and bottom right, respectively); companion CT (bottom left);and fusion I-124 PUH71 PET-CT (top left).

FIG. 2: I-124 PUH71 PET-CT of a chronic pulmonary infiltrate in a 59year old woman with ovarian cancer. Shown is a 3-dimensional maximumintensity projection (MIP) PET image of a portion of the patient's body,spanning from the skull base to the lower chest region. The PET imageshows distinct accumulation of 1-124 PUH71 in an inflammatory pulmonaryinfiltrate (arrow) in the apex of the patient's left lung. PET-CTimaging was performed 24 hours after intravenous injection of 9.3 mCi1-124 PUH71.

FIGS. 3 and 4: I-124 PUH71 PET-CT of a pulmonary consolidation in a 49year old woman with breast cancer. Shown are corresponding serial PETand CT images of a single transaxial plane through the patient's chest(FIG. 3), and 3-dimensional maximum intensity projection (MIP) PETimages of a portion of the patient's chest (FIG. 4) obtained at threedifferent time-points after a single injection of 6.5 mCi I-124 PUH71mixed with a therapeutic dose of 35 mg non-radioactive PUH71:immediately (left column), 4 hours (middle column) and 24 hours (rightcolumn), post-injection. PET image intensity at all time points isscaled by the same window settings (upper threshold: 5.00 kBq/mL, lowerthreshold: 0.00 kBq/mL). An inflammatory pulmonary consolidation in theright lung (arrow) demonstrates distinct accumulation and sustainedretention of I-124 PUH71 at all time points, after tracer has clearedfrom blood stream (double arrow points at void of activity within thecardiac atrium; distinct tracer retention in adjacent left ventriclemyocardium also visualized). Patient had a large right pleural effusion(arrowhead). In addition to receiving an ongoing therapeutic regimen ofPUH71 (three week cycles of 35 mg twice a week for two weeks, then nodose for one week), the patient received antibiotic treatment andpleural fluid drainage. Two weeks after these images were taken, a CTscan showed the pulmonary consolidation had resolved.

DEFINITIONS

Certain compounds of the present disclosure, and definitions of specificfunctional groups are described in more detail below. For purposes ofthis disclosure, the chemical elements are identified in accordance withthe Periodic Table of the Elements, CAS version, Handbook of Chemistryand Physics, 75^(th) Ed., inside cover, and specific functional groupsare generally defined as described therein. Additionally, generalprinciples of organic chemistry, as well as specific functional moietiesand reactivity, are described in “Organic Chemistry”, Thomas Sorrell,University Science Books, Sausalito: 1999, the entire contents of whichare incorporated herein by reference.

As used herein, the following definitions shall apply unless otherwiseindicated.

The term “aliphatic” or “aliphatic group,” as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic, bicyclic orpolycyclic hydrocarbon that is completely saturated or that contains oneor more units of unsaturation, but which is not aromatic (also referredto herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has asingle point of attachment to the rest of the molecule. Unless otherwisespecified, aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-12 aliphatic carbon atoms. Insome embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms.In some embodiments, aliphatic groups contain 1-5 aliphatic carbonatoms. In other embodiments, aliphatic groups contain 1-4 aliphaticcarbon atoms. In still other embodiments, aliphatic groups contain 1-3aliphatic carbon atoms, and in yet other embodiments, aliphatic groupscontain 1-2 aliphatic carbon atoms. In some embodiments,“cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to amonocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent.

The term “alkynylene” refers to a bivalent alkynyl group. A substitutedalkynylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent.

The term “acyl,” used alone or a part of a larger moiety, refers togroups formed by removing a hydroxy group from a carboxylic acid.

The term “halogen” means F, Cl, Br, or I.

The terms “aralkyl” and “arylalkyl” are used interchangeably and referto alkyl groups in which a hydrogen atom has been replaced with an arylgroup. Such groups include, without limitation, benzyl, cinnamyl, anddihydrocinnamyl.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclicor polycyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic and whereineach ring in the system contains 3 to 7 ring members. The term “aryl”may be used interchangeably with the term “aryl ring.”

In certain embodiments of the present disclosure, “aryl” refers to anaromatic ring system which includes, but not limited to, phenyl,biphenyl, naphthyl, anthracyl and the like, which may bear one or moresubstituents. Also included within the scope of the term “aryl,” as itis used herein, is a group in which an aromatic ring is fused to one ormore non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl,phenanthridinyl, or tetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 14 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Non-limiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The terms “heteroaralkyl” and “heteroarylalkyl”refer to an alkyl group substituted by a heteroaryl moiety, wherein thealkyl and heteroaryl portions independently are optionally substituted.

The term “heteroaliphatic,” as used herein, means aliphatic groupswherein one or more carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, or phosphorus. Heteroaliphatic groupsmay be substituted or unsubstituted, branched or unbranched, cyclic oracyclic, and include “heterocycle,” “heterocyclyl,”“heterocycloaliphatic,” or “heterocyclic” groups.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclicring” are used interchangeably and refer to a stable 3- to 14-memberedmonocyclic or 7-14-membered bicyclic or polycyclic heterocyclic moietythat is either saturated or partially unsaturated, and having, inaddition to carbon atoms, one or more, preferably one to four,heteroatoms, as defined above. When used in reference to a ring atom ofa heterocycle, the term “nitrogen” includes a substituted nitrogen. Asan example, in a saturated or partially unsaturated ring having 0-3heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen maybe N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR(as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterm “heterocycle” also includes groups in which a heterocyclyl ring isfused to one or more aryl, heteroaryl, or cycloaliphatic rings, such asindolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As used herein and in the claims, the singular forms “a”, “an”, and“the” include the plural reference unless the context clearly indicatesotherwise. Thus, for example, a reference to “a compound” includes aplurality of such compounds.

In another aspect, the present disclosure provides “pharmaceuticallyacceptable” compositions, which comprise a therapeutically effectiveamount of one or more of the compounds described herein, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail, the pharmaceuticalcompositions of the present disclosure may be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets, e.g., those targeted forbuccal, sublingual, and systemic absorption, boluses, powders, granules,pastes for application to the tongue; parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; topical application, for example, as acream, ointment, or a controlled-release patch or spray applied to theskin, lungs, or oral cavity; intravaginally or intrarectally, forexample, as a pessary, cream or foam; sublingually; ocularly;transdermally; or nasally, pulmonary and to other mucosal surfaces.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, or solvent encapsulatingmaterial, involved in carrying or transporting the subject compound fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol;pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides;and other non toxic compatible substances employed in pharmaceuticalformulations.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each stereocenter, Z and E double bond isomers, and Zand E conformational isomers. Therefore, single stereochemical isomersas well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the disclosure. Unless otherwise stated, all tautomeric forms of thecompounds of the disclosure are within the scope of the disclosure.

Provided compounds may comprise one or more saccharide moieties. Unlessotherwise specified, both D- and L-configurations, and mixtures thereof,are within the scope of the disclosure. Unless otherwise specified, bothα- and β-linked embodiments, and mixtures thereof, are contemplated bythe present disclosure.

If, for instance, a particular enantiomer of a compound of the presentdisclosure is desired, it may be prepared by asymmetric synthesis,chiral chromatography, or by derivation with a chiral auxiliary, wherethe resulting diastereomeric mixture is separated and the auxiliarygroup cleaved to provide the pure desired enantiomers. Alternatively,where the molecule contains a basic functional group, such as amino, oran acidic functional group, such as carboxyl, diastereomeric salts areformed with an appropriate optically-active acid or base, followed byresolution of the diasteromers thus formed by fractional crystallizationor chromatographic means well known in the art, and subsequent recoveryof the pure enantiomers.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present disclosure.

As described herein, compounds of the disclosure may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this disclosure arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —(CH₂)₀₋₄SR^(o); (CH₂)₀₋₄S(O)R^(o);—(CH₂)₀₋₄S(O)₂R^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄O—(CH₂)₀₋₁pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR^(o); —SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o);—(CH₂)₀₋₄C(O)NR^(o) ₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —SC(S)SR^(o),—(CH₂)₀₋₄OC(O)NR^(o) ₂; —C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o);—(CH₂)₀₋₄S(O)₂R^(o); —(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o);—S(O)₂NR^(o) ₂; —(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂;N(R^(o))S(O)₂R^(o); —N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o);—P(O)R^(o) ₂; —OP(O)R^(o) ₂; —OP(O)(OR^(o))₂; —PR^(o) ₂; —OPR^(o) ₂;—SiR^(o) ₃; —OSiR^(o) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)ON(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6-membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(●) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R^(*) ₂))₂₋₃O—,or —S(C(R^(*) ₂))₂₋₃S—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents thatare bound to vicinal substitutable carbons of an “optionallysubstituted” group include: O(CR^(*) ₂)₂₋₃O, wherein each independentoccurrence of R* is selected from hydrogen, C₁₋₆ aliphatic which may besubstituted as defined below, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include R†, NR†_(z), C(O)R†, C(O)OR†, C(O)C(O)R†,C(O)CH₂C(O)R†, —S(O)₂R†, —S(O)₂NR†₂, —C(S)NR†₂, —C(NH)NR†₂, or—N(R†)S(O)₂R†; wherein each R† is independently hydrogen, C₁₋₆ aliphaticwhich may be substituted as defined below, unsubstituted —OPh, or anunsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, notwithstanding the definition above, twoindependent occurrences of R†, taken together with their interveningatom(s) form an unsubstituted 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of Rt are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “labeled compound” refers to a compound thatproduces an enhanced signal compared to the compound prior to labelingwhen detected by a medical imaging technique. A labeled compound mayhave one or more “labels”, which is an atom or moiety that leads to anenhanced signal. In some embodiments, a labeled compound isradiolabelled, wherein the labeled compound contains one or moreenriched radioactive isotopes of at least one element. Exemplarysuitable isotopes include but are not limited to those used in positronemission tomography (PET) such as ¹²⁴I, ¹¹C, ¹⁵O, ¹³N and ¹⁸F; and thoseused in single-photon emission computed tomography (SPECT). In someembodiments, a labeled compound is labeled with one or morenon-radioactive labels. In some embodiments, a non radioactive label canbe detected by Magnetic Resonance Imaging (MRI). In some embodiments,the non-radioactive label is ¹⁹F. In some embodiments, a label is suitedfor MRI. In some embodiments, the label is a contrast agent. Manymethods are known in the art for compound labeling. In some embodiments,a compound is labeled by substituting a hydrogen atom with a label. Insome embodiments, a compound is labeled by substituting a hydrogen atomwith a suitable fluorine or iodine label. In some embodiments, asuitable fluorine label is ¹⁸F. In some embodiments, a suitable fluorinelabel is ¹⁹F. In some embodiments, a suitable iodine label is ¹²³I. Insome embodiments, a suitable iodine label is ¹²⁴I. In some embodiments,a suitable iodine label is ¹²⁵I. In some embodiments, a suitable iodinelabel is ¹³¹I. In some embodiments, a label comprises more than oneatom. In some other embodiments, a compound is labeled by altering theisotopic composition of one or more atoms, often by increasing thepercentage of the isotope(s) that can be detected by the medical imagingtechnique to be used (“enriched”). In some embodiments, a labeledcompound is isotopically enriched in one of ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ¹¹C,¹⁵O, ¹³N, and ¹⁸F or their combinations thereof. In some embodiments, alabeled compound is isotopically enriched in ¹²³I. In some embodiments,a labeled compound is isotopically enriched in ¹²⁴I. In someembodiments, a labeled compound is isotopically enriched in ¹²⁵I. Insome embodiments, a labeled compound is isotopically enriched in ¹³¹I.In some embodiments, a labeled compound is isotopically enriched in ¹¹C.In some embodiments, a labeled compound is isotopically enriched in ¹⁵O.In some embodiments, a labeled compound is isotopically enriched in ¹³N.In some embodiments, a labeled compound is isotopically enriched in ¹⁸F.In some embodiments, a labeled compound comprises more than one label.In some embodiments, a labeled compound can be detected by one or moremedical imaging techniques, for example but not limited to MRI, PET andSPECT. In some embodiments, a labeled compound comprises more than oneradioactive label. In some embodiments, a labeled compound comprisesmore than one fluorine label. In some embodiments, a labeled compoundcomprises more than one ¹⁹F. In some embodiments, a label is afluorophore moiety. In some embodiments, a label is a nanometer-sizedagent. In some embodiments, a label is a nanoparticle. In someembodiments, a label is a nanotube. In some embodiments, a label isliposome. In some embodiments, a nanotube or liposome comprises a moietythat produces an enhanced signal. In some embodiments, one or more MRIagents are linked or packaged in a nanotube, nanoparticle or liposome.In some embodiments, one nanometer-sized agent or nanoparticle orliposomal micelle is used to label more than one molecule of a compoundto be labeled; for example, more than one molecule of the compound to belabeled can be linked to a single nanoparticle. In some embodiments, alabel is covalently linked to a compound. In some embodiments, a labelis non-covalently linked to a compound.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

The term “palliative” refers to treatment that is focused on the reliefof symptoms of a disease and/or side effects of a therapeutic regimen,but is not curative.

As used herein, the term “therapeutically effective amount” means anamount of a substance (e.g., a therapeutic agent, composition, and/orformulation) that elicits a desired biological response whenadministered as part of a therapeutic regimen. In some embodiments, atherapeutically effective amount of a substance is an amount that issufficient, when administered to a subject suffering from or susceptibleto a disease, disorder, and/or condition, to treat the disease,disorder, and/or condition. As will be appreciated by those of ordinaryskill in this art, the effective amount of a substance may varydepending on such factors as the desired biological endpoint, thesubstance to be delivered, the target cell or tissue, etc. For example,the effective amount of compound in a formulation to treat a disease,disorder, and/or condition is the amount that alleviates, ameliorates,relieves, inhibits, prevents, delays onset of, reduces severity ofand/or reduces incidence of one or more symptoms or features of thedisease, disorder, and/or condition. In some embodiments, atherapeutically effective amount is administered in a single dose; insome embodiments, multiple unit doses are required to deliver atherapeutically effective amount.

As used herein, an “inflammation” means a disease, disorder, orcondition characterized by inflammation of body tissue or having aninflammatory component. These include local inflammatory responses andsystemic inflammation. Examples of such inflammatory disorders include:transplant rejection, including skin graft rejection; chronicinflammatory disorders of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases such as ileitis, ulcerativecolitis, Barrett's syndrome, and Crohn's disease; inflammatory lungdisorders such as asthma, adult respiratory distress syndrome, andchronic obstructive airway disease; inflammatory disorders of the eyeincluding corneal dystrophy, trachoma, onchocerciasis, uveitis,sympathetic ophthalmitis and endophthalmitis; chronic inflammatorydisorders of the gums, including gingivitis and periodontitis;tuberculosis; leprosy; inflammatory diseases of the kidney includinguremic complications, glomerulonephritis and nephrosis; inflammatorydisorders of the skin including sclerodermatitis, psoriasis and eczema;inflammatory diseases of the central nervous system, including chronicdemyelinating diseases of the nervous system, multiple sclerosis,AIDS-related neurodegeneration and Alzheimer's disease, infectiousmeningitis, encephalomyelitis, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis and viral or autoimmuneencephalitis; autoimmune disorders, immune-complex vasculitis, systemiclupus and erythematodes; systemic lupus erythematosus (SLE); andinflammatory diseases of the heart such as cardiomyopathy, ischemicheart disease hypercholesterolemia, atherosclerosis; as well as variousother diseases with significant inflammatory components, includingpreeclampsia; chronic liver failure, brain and spinal cord trauma, andcancer. There may also be a systemic inflammation of the body,exemplified by gram-positive or gram negative shock, hemorrhagic oranaphylactic shock, or shock induced by cancer chemotherapy in responseto pro-inflammatory cytokines, e.g., shock associated withpro-inflammatory cytokines. Such shock can be induced, e.g., by achemotherapeutic agent used in cancer chemotherapy. In some embodiments,“treatment of an inflammatory disorder” includes administering adescribed compound or a composition to a subject who has an inflammatorydisorder, a symptom of such a disorder, or a predisposition towards sucha disorder, with the purpose to cure, relieve, alter, affect, or preventthe inflammatory disorder, the symptom of it, or the predispositiontowards it.

As used herein, an “infection” means a disease, disorder or condition,caused by one or more microorganisms, including but not limited toviruses, bacteria, fungi, and parasites. In some embodiments, theinfection is a bacterial infection (e.g., infection by E. coli,Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp.,Staphylococcus aureus, Streptococcus spp., or vancomycin-resistantenterococcus). In certain embodiments, the infection is a fungalinfection (e.g., infection by a mould, a yeast, or a higher fungus). Insome embodiments, the infection is a parasitic infection (e.g.,infection by a single-celled or multicellular parasite, includingGiardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, andToxoplasma gondii). In some embodiments, the infection is a viralinfection (e.g., infection by a virus associated with AIDS, avian flu,chickenpox, cold sores, common cold, gastroenteritis, glandular fever,influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, andlower or upper respiratory tract infection (e.g., respiratory syncytialvirus)).

As used herein, the term “treat,” “treatment,” or “treating” refers toany method used to partially or completely alleviate, ameliorate,relieve, inhibit, prevent, delay onset of, reduce severity of and/orreduce incidence of one or more symptoms or features of a disease,disorder, and/or condition. In some embodiments, the term “treatment”refers to treatment of an inflammation and/or infection with theanti-inflammatory drugs and/or anti-infection drug provided herein.Treatment may be administered to a subject who does not exhibit signs ofa disease, disorder, and/or condition. In some embodiments, treatmentmay be administered to a subject who exhibits only early signs of thedisease, disorder, and/or condition for the purpose of decreasing therisk of developing pathology associated with the disease, disorder,and/or condition. Daily usage of a formulation of the present inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularsubject or organism may depend upon a variety of factors including thedisorder being treated and the severity of the disorder; activity ofspecific active compound employed; specific composition employed; age,body weight, general health, sex and diet of the subject; time ofadministration, and rate of excretion of the specific active compoundemployed; duration of the treatment; drugs and/or additional therapiesused in combination or coincidental with specific compound(s) employed,and like factors well known in the medical arts. A particular unit dosemay or may not contain a therapeutically effective amount of atherapeutic agent.

The expression “unit dose” as used herein refers to a physicallydiscrete unit of a formulation appropriate for a subject to be treated.It will be understood, however, that the total daily usage of aformulation of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism may dependupon a variety of factors including the disorder being treated and theseverity of the disorder; activity of specific active compound employed;specific composition employed; age, body weight, general health, sex anddiet of the subject; time of administration, and rate of excretion ofthe specific active compound employed; duration of the treatment; drugsand/or additional therapies used in combination or coincidental withspecific compound(s) employed, and like factors well known in themedical arts. A particular unit dose may or may not contain atherapeutically effective amount of a therapeutic agent.

An individual who is “suffering from” a disease, disorder, and/orcondition has been diagnosed with and/or displays one or more symptomsof the disease, disorder, and/or condition.

An individual who is “susceptible to” a disease, disorder, and/orcondition has not been diagnosed with the disease, disorder, and/orcondition. In some embodiments, an individual who is susceptible to adisease, disorder, and/or condition may exhibit symptoms of the disease,disorder, and/or condition. In some embodiments, an individual who issusceptible to a disease, disorder, and/or condition may not exhibitsymptoms of the disease, disorder, and/or condition. In someembodiments, an individual who is susceptible to a disease, disorder,and/or condition will develop the disease, disorder, and/or condition.In some embodiments, an individual who is susceptible to a disease,disorder, and/or condition will not develop the disease, disorder,and/or condition.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The present invention encompasses the recognition of the importance todevelop new methods for imaging tissue inflammation and/or infection,for the diagnosis, treatment, or prevention of an inflammation and/orinfection, for monitoring the effect of an inflammation and/or infectiontreatment, for selecting subjects for an inflammation and/or infectiontreatment, and for determining drug dosages. The present inventionprovides, among other things, novel methods for the aforementionedpurposes.

Hsp90 has been found to be associated with inflammation and infection(Barabutis N et al. Am J Physiol Lung Cell Mol Physiol. 2013 Jun. 15;304(12):L883-93; Bohonowych J E et al. Prostate. 2014 April;74(4):395-407; Kakeda M et al. J Am Acad Dermatol. 2014 April;70(4):683-690; Wang C et al. Nat Immunol. 2013 January; 14(1):72-81;Thangjam G S et al. Am J Respir Cell Mol Biol. 2014 May; 50(5):942-52;Collins C B et al. Inflamm Bowel Dis. 2014 April; 20(4):685-94; Chen Det al. Biochem Biophys Res Commun. 2014 Jan. 3; 443(1):326-32; ShebrainS, Ramjit A. J Surg Res. 2013 November; 185(1):e53-4; Collins C B et al.Mucosal Immunol. 2013 September; 6(5):960-71). While Hsp90 may berelated to inflammation and infection, prior to the present disclosure,methods of identifying patients most likely to benefit from Hsp90therapy in these indications were unknown.

The present invention encompasses the recognition that it is importantto be able to define a patient subpopulation that should receive atreatment in order to engender successful development of targetingagents for therapy. Such selection may reduce the number of patientsreceiving ineffective treatment, as well as minimize the over- orimproper use of drug treating infection, which can lead to resistance.In some embodiments, the present invention provides methods ofdetermining whether a patient has an inflammation or infection. In someembodiments, the present invention provides a method of assaying thepresence of Hsp90 in an inflammation and/or infection. In someembodiments, the present invention provides a method of assaying anHsp90-mediated inflammation and/or infection.

As previously described by Applicant in WO2013/009655, the entirecontents of which are incorporated herein by reference, “oncogenicHsp90” is a cell stress-specific form of Hsp90 that is expanded andconstitutively maintained in the tumor cell context, and that mayexecute functions necessary to maintain the malignant phenotype. Withoutwishing to be bound by any particular theory, the present inventionencompasses the recognition that a related form of Hsp90 observed in thetumor context can also be observed in tissue affected by an inflammationand/or infection (i.e., stress-specific Hsp90) using methods providedherein. In such a case, it is believed that tissue affected by aninflammation and/or infection comprising stress-specific Hsp90 has agreater likelihood of benefiting from treatment with Hsp90 inhibitors.In some embodiments, provided methods are useful for detecting andtreating an inflammation and/or infection, wherein a higher uptake of anHsp90-targeting imaging agent indicates a higher likelihood a patientwill benefit from Hsp90 inhibitor therapy. The generated imagery depictsaffected tissues in the subject as sites of high or low levels of signalfrom the labeled compound relative to surrounding healthy tissues in thesame organ; or alternatively, depicts an organ with diffuseinfectious/inflammatory disease as an organ with diffuse,relatively-high or -low level of signal, compared to the level of signalvisualized in that organ in other healthy subjects.

A stressed cell, i.e., a cell under stress caused by or associated withinflammation and/or infection, contains a complex mixture of Hsp90complexes. While a majority of Hsp90 complexes perform “housekeeping”chaperone functions similarly to non-stressed, normal cells, afunctionally distinct fraction of Hsp90 buffers the cell's proteomealtered in the stress process (i.e., stress-specific Hsp90).“Stress-specific Hsp90” as used herein means a form of Hsp90 expressedin response to inflammation and/or infection. Such stress-specific Hsp90is the fraction of Hsp90 that is expanded and constitutively maintainedin the inflamed and/or infected cell context, and that specificallyinteracts with inflammation/infection proteins required to cause ormaintain an inflamed or infected cell state, aberrant proliferativefeatures, and/or invasive behavior.

Stress-specific Hsp90 manifests in response to the altered proteome thatarises in inflamed and/or infected cells, and may differ fromhousekeeping or other forms of Hsp90 by way of chemical modifications(e.g., post-translational modifications) or biochemical modifications(e.g., co-chaperone and adapter protein recruitment), by way ofnonlimiting example. Indeed, different types of cell stress can engenderdifferent stress forms of Hsp90. Without wishing to be bound by anyparticular theory, it is believed that when inflammation and/orinfection becomes reliant upon a Hsp90 inflammation/infection proteome,this proteome becomes dependent on “stress-specific Hsp90” forfunctioning and stability. This symbiotic interdependence suggests thatreliance of inflammation and/or infection on an Hsp90inflammation/infection proteome equals reliance on “stress-specificHsp90”. Measuring the abundance of the latter is a read-out of thefirst, and therefore, in accordance with the present disclosure, is abiomarker for Hsp90 therapy enrichment. In some embodiments, providedare methods of identifying and measuring the abundance of thisstress-specific Hsp90 species in inflammation and/or infection forpredicting response to Hsp90 therapy.

The present disclosure encompasses the recognition that certain smallmolecule compounds selectively interact with stress-specific Hsp90. Insome embodiments, a labeled compound as disclosed herein binds tostress-specific Hsp90. In some embodiments, a labeled compoundspecifically binds to stress-specific Hsp90. In some embodiments, alabeled compound binds to a stress-specific form of Hsp90 selectivelyover a housekeeping form of Hsp90 (i.e., a form characterized by normalchaperone functions and/or not predominantly expressed in response totissue stress caused by or associated with inflammation or infection).

In some embodiments, a labeled compound inhibits stress-specific Hsp90.In some embodiments, a labeled compound selectively inhibitsstress-specific Hsp90. In some embodiments, a labeled compound inhibitsa stress specific form of Hsp90 selectively over a housekeeping form ofHsp90.

In some embodiments, a labeled compound binds to stress-specific Hsp90selectively over a housekeeping form of Hsp90. In some embodiments, aratio of binding stress-specific Hsp90 to a housekeeping form of Hsp90of about 1.5 or greater indicates that an inflammation/infection patientwill be susceptible to Hsp90 inhibition therapy. In some embodiments, aratio of binding stress-specific Hsp90 to a housekeeping form of Hsp90of about 2 or greater indicates that an inflammation/infection patientwill be susceptible to Hsp90 inhibition therapy. In some embodiments, aratio of binding stress-specific Hsp90 to a housekeeping form of Hsp90of about 2.5 or greater indicates that an inflammation/infection patientwill be susceptible to Hsp90 inhibition therapy. In some embodiments, aratio of binding stress-specific Hsp90 to a housekeeping form of Hsp90of about 3 or greater indicates that an inflammation/infection patientwill be susceptible to Hsp90 inhibition therapy. In some embodiments, aratio of binding stress-specific Hsp90 to a housekeeping form of Hsp90of about 4 or greater indicates that an inflammation/infection patientwill be susceptible to Hsp90 inhibition therapy. In some embodiments, aratio of binding stress-specific Hsp90 to a housekeeping form of Hsp90of about 5 or greater indicates that an inflammation/infection patientwill be susceptible to Hsp90 inhibition therapy.

It will be appreciated that in some embodiments, the methods describedherein may be conducted by imaging at the cellular level. This can beadvantageous in certain contexts, for example infectious disease ofblood cells, where imaging detects signals coming from individualscells. In some embodiments, such methods further comprise collecting atissue sample from a subject prior to imaging. In some embodiments, alabeled compound used in such methods comprises a fluorescent label. Insome embodiments, the imaging comprises FACS.

In some embodiments, a ratio of binding inflamed/infected cells tonormal cells of about 1.5 or greater indicates that aninflammation/infection patient will be susceptible to Hsp90 inhibitiontherapy. In other embodiments, a ratio of binding inflamed/infectedcells to normal cells of about 2 or greater indicates that aninflammation/infection patient will be susceptible to Hsp90 inhibitiontherapy. In still other embodiments, a ratio of bindinginflamed/infected cells to normal cells of about 2.5 or greaterindicates that an inflammation/infection patient will be susceptible toHsp90 inhibition therapy. In still other embodiments, a ratio of bindinginflamed/infected cells to normal cells of about 3 or greater indicatesthat an inflammation/infection patient will be susceptible to Hsp90inhibition therapy. In still other embodiments, a ratio of bindinginflamed/infected cells to normal cells of about 4 or greater indicatesthat an inflammation/infection patient will be susceptible to Hsp90inhibition therapy. In still other embodiments, a ratio of bindinginflamed/infected cells to normal cells of about 5 or greater indicatesthat an inflammation/infection patient will be susceptible to Hsp90inhibition therapy.

It has been found that the labeled compounds that bind to Hsp90 asprovided herein have a sustained retention in inflamed/infected tissue.In some embodiments, a labeled compound provided herein has been foundto sustain in a lesion after uptake, relative to its clearance from theblood and surrounding healthy tissues. As such, imaging methods usingthe labeled compound provided herein have a number of advantages,including greater clarity of lesion uptake, higher lesion-to-backgroundratio, and improved clarity over time of detectable signal.

The present invention encompasses the recognition that methods fordetecting the existence and location of an infection or inflammation areuseful in a clinical setting for the timely diagnosis and treatment ofinfection or inflammation. This is particularly the case when infectionor inflammation resides in an internal tissue. In some embodiments, thepresent invention is useful in this context and can be used to detectinflammation and/or infection at an earlier stage than other methods. Insome embodiments, provided methods are used to detect inflammationand/or infection at less than about 12 hours, 11 hours, 10 hours, 9hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or1 hour post-administration of a labeled compound. In some embodiments,provided methods allow for same-day diagnosis of an inflammation and/orinfection. As shown by FIGS. 3 and 4, using labeled PUH71 as aradiotracer, an inflammation/infection can be detected in about 4 hoursafter the injection of the radiotracer. Without wishing to be bound byany theory, this advantage of early detection is contributed to not onlyby PUH71's high uptake relative to surrounding healthy tissues and itssustained retention in the diseased tissue, but also its rapid bloodclearance.

It will be appreciated that in other contexts, imaging or reimaginginflammation and/or infection at later timepoints w/o additionaladministration of labeled compound is advantageous. For example, aclinician may desire to obtain additional scans for confirmation orclarification of prior scans, or to monitor treatment efficacy. In someembodiments, provided methods are used to detect inflammation and/orinfection at more than about 12 hours, 15 hours, 18 hours, 20 hours, 24hours, 36 hours, 48 hours, 72 hours, 96 hours, a week, or more afterinjection of a labeled compound. As shown by FIGS. 1-4, using labeledPUH71 as a radiotracer, an inflammation/infection can be detected atleast about 24 hours after the injection of the radiotracer.

In some embodiments, the present invention provides a method of imaginga tissue affected by inflammation and/or infection in a subject in needthereof, comprising steps of:

(a) administering to the subject a labeled compound that binds to Hsp90;and

(b) imaging the tissue by detecting the labeled compound in the subject.

Compounds that bind to Hsp90 and methods of labeling the same are knownin the art and familiar to the skilled artisan. Non-limiting examples ofcompounds that bind to Hsp90 and may be labeled are described by Taldoneet al, Expert Opin Ther Pat, 24(5): 501-18 (2014), the entire contentsof which are hereby incorporated by reference.

In some embodiments, the method further comprises detecting the presenceof the inflammation and/or infection in the tissue by analyzing theimage obtained in step (b).

In some embodiments, the present invention provide a method for imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

(a) administering to the subject a labeled compound of any of formula Ito IX as described in the specification; and(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the method further comprises detecting the presenceof the inflammation and/or infection in the tissue by analyzing theimage obtained in step (b).

In some embodiments, the present invention provides a method of imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

-   -   (a) administering to the subject an effective amount of a        labeled compound of formula I:

-   -   or its pharmaceutically acceptable salt thereof, wherein:    -   each Y is independently CH or N;    -   R is hydrogen, a C₁ to C₁₀ alkyl, alkenyl, alkynyl, or an        alkoxyalkyl group, optionally comprising one or more        heteroatoms, or a targeting moiety connected to N9 via a linker;        -   X₄ is hydrogen or halogen;        -   X₃ is CH₂, CF₂, S, SO, SO₂, O, NH, or NR², wherein R² is            alkyl;        -   X₂ is halogen, alkyl, alkoxy, halogenated alkoxy,            hydroxyalkyl, pyrollyl, optionally substituted aryloxy,            alkylamino, dialkylamino, carbamyl, amido, alkylamido,            dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy,            trihalocarbon, thioalkyl, C(O)O-alkyl, NH₂, OH, CN, SO₂X₅,            NO₂, NO, C(S)R, NHSO₂X₅, or C(O)R, where X₅ is F, NH₂,            alkyl, or H, and R² is alkyl, NH₂, NH-alkyl, or O-alkyl; and        -   X₁ represents two substituents, which may be the same or            different, disposed in the 4′ and 5′ positions on the awl            group, wherein X₁ is selected from halogen, alkyl, alkoxy,            halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally            substituted aryloxy, alkylamino, dialkylamino, carbamyl,            amido, alkylamido, dialkylamido, acylamino,            alkylsulfonylamido, trihalomethoxy, trihalocarbon,            thioalkyl, COO-alkyl, NH₂OH, CN, SO₂X₅, NO₂, NO, C(S)R,            NHSO₂X₅, or C(O)R₂, where X₅ is F, NH₂, alkyl, or H, and R²            is alkyl, NH₂, NH-alkyl, or O-alkyl, C₁ to C₆ alkyl or            alkoxy, or wherein X₁ has the formula —O—(CH₂)_(m)O—,            wherein n is an integer from 1 to 2, and one of the oxygens            is bonded at the 5′-position and the other at the            4′-position of the aryl ring; and        -   (b) imaging the tissue by detecting the labeled compound in            the subject.

In some embodiments of a labeled compound of formula 1, each hydrogen isoptionally and independently substituted with a group that can bedetected by a medical imaging technique, and/or at least one atom isoptionally enriched in an isotope that can be detected by a medicalimaging technique.

In some embodiments, a labeled compound of formula I is a labeledcompound having the structure of formula II,

wherein Y′ is —CH₂— or S;

X₄ is hydrogen or halogen; and R is an amino alkyl moiety, optionallysubstituted on the amino nitrogen with one or two carbon-containingsubstituents selected independently from the group consisting of alkyl,alkenyl, and alkynyl substituents, wherein the total number of carbonsin the amino alkyl moiety is from 1 to 9.

In some embodiments, the present invention provides a method of imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

(a) administering to the subject an effective amount of a labeledcompound of formula III or IV:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   (a) each of Z₁, Z₂ and Z₃ is independently CH or N;    -   (b) Y is CH₂, O, or S;    -   (c) Xa, Xb, Xc, and Xd are independently selected from CH, CH₂,        O, N, NH, S, carbonyl, fluoromethylene, and difluoromethylene        selected so as to satisfy valence, wherein each bond to an X        group is either a single bond or a double bond;    -   (d) X₂ is ¹²³I, ¹²⁴I, ¹²⁵I, or ¹³¹I;    -   (e) X₄ is hydrogen or halogen; and    -   (f) R is straight-chain- or branched-substituted or        unsubstituted alkyl, straight-chain- or branched-substituted or        unsubstituted alkenyl, straight-chain- or branched-substituted        or unsubstituted alkynyl, or substituted or unsubstituted        cycloalkyl, wherein the R group is optionally interrupted by        —S(O)N(R_(A))—, —NR_(A)S(O)—, —SO₂N(R_(A))—, —NR_(A)SO₂—,        —C(O)N(R_(A))—, or —NR_(A)C(O)—, and/or the R group is        optionally terminated by —S(O)NR_(A)R_(B), —NR_(A)S(O)R_(B),        —SO₂NR_(A)R_(B), —NR_(A)SO₂R_(B), —C(O)NR_(A)R_(B), or        —NR_(A)C(O)R_(B), wherein each R_(A) and R_(B); is independently        selected from hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆        alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl,        heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl,        heteroarylalkyl, and alkylheteroarylalkyl; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method of imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

(a) administering to the subject an effective amount of a labeledcompound of formula III or IV:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   (a) each of Z₁, Z₂ and Z₃ is independently CH or N;    -   (b) Y is CH₂, O, or S;    -   (c) Xa, Xb, Xc, and Xd are independently selected from CH, CH₂,        O, N, NH, S, carbonyl, fluoromethylene, and difluoromethylene        selected so as to satisfy valence, wherein each bond to an X        group is either a single bond or a double bond;    -   (d) X₂ is ¹²¹I, ¹²⁴I, ¹²⁵I, or ¹³¹I;    -   (e) X₄ is hydrogen or halogen; and    -   (f) R is —(CH₂)_(m)N—R₁₀R₁₁R₁₂ or —(CH₂)_(m)—N—R₁₀R₁₁, where m        is 2 or 3 and where R₁₀-R₁₂ are independently selected from        hydrogen, methyl, ethyl, ethenyl, ethynyl, propyl, hydroxyalkyl,        isopropyl, t-butyl, isobutyl, cyclopentyl, a 3-membered ring        including the nitrogen, or a 6-membered ring including the        nitrogen and optionally an additional heteroatom with        substituents to satisfy valence, with the proviso that when all        of R₁₀-R₁₂ are present the compound further comprises a        pharmaceutically acceptable counter ion; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method of imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

(a) administering to the subject an effective amount of a labeledcompound of formula V:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y is CH₂ or S;    -   X₄ is H or halogen    -   X₂ is ¹²³I, ¹²⁴I, ¹²⁵I, or ¹³¹I; and    -   R is —(CH₂)_(m) N—R₁₀R₁₁R₁₂ or —(CH₂)_(m)—N—R₁₀R₁₁, where m is 2        or 3 and where R₁₀-R₁₂ are independently selected from hydrogen,        methyl, ethyl, ethenyl, ethynyl, propyl, hydroxyalkyl,        isopropyl, t-butyl, isobutyl, cyclopentyl, a 3-membered ring        including the nitrogen, or a 6-membered ring including the        nitrogen and optionally an additional heteroatom with        substituents to satisfy valence, with the proviso that when all        of R₁₀-R₁₂ are present the compound further comprises a        pharmaceutically acceptable counter ion; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method of imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

(a) administering to the subject an effective amount of a labeledcompound of formula VI:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y is CH₂ or S;    -   X₄ is H or halogen;    -   X₂ is ¹²³I, ¹²⁴I, ¹²⁵I, or ¹³¹I; and    -   R is 2-ethanesulfonic acid isopropylamide, 2-ethanesulfonic acid        ethylamide, 2-ethanesulfonic acid methylamide, 2-ethanesulfonic        acid amide, 2-ethanesulfonic acid t-butylamide, 2-ethanesulfonic        acid isobutylamide, 2-ethanesulfonic acid cyclopropylamide,        isopropanesulfonic acid 2-ethylamide, ethanesulfonic acid        2-ethylamide, N-2 ethyl methanesulfonamide,        2-methyl-propane-2-sulfonic acid 2-ethylamide,        2-methyl-propane-2-sulfinic acid 2-ethylamide,        2-methyl-propane-1-sulfonic acid 2-ethyl amide,        cyclopropanesufonic acid 2-ethylamide, 3-propane-1-sulfonic acid        isopropylamide, 3-propane-1-sulfonic acid ethylamide,        3-propane-1-sulfonic acid methylamide, 3-propane-1-sulfonic acid        amide, 3-propane-1-sulfonic acid t-butylamide,        3-propane-1-sulfonic acid isobutylamide, 3-propane-1-sulfonic        acid cyclopropylamide, propane-2-sulfonic acid 3-propylamide,        ethanesulfonic acid 3-propylamide, N-3-propyl        methanesulfonamide, 2-methyl-propane-2-sulfonic acid        3-propylamide, 2-methyl-propane-2-sulfinic acid 3-propylamide,        2-methyl-propane-1-sulfonic acid 3-propylamide,        cyclopropanesulfonic acid 3-propylamide, 3-N-isopropyl        propionamide, 3-N-ethyl propionamide, 3-N-methyl propionamide,        3-propionamide, 3-N-t-butyl propionamide, 3-N-isobutyl        propionamide, 3-N-cyclopropyl propionamide, N-2-ethyl        isobutyramide, N-2-ethyl propionamide, N-2-ethyl acetamide,        N-2-ethyl formamide, N-2-ethyl 2,2-dimethyl-propionamide,        N-2-ethyl 3-methylbutyramide, or cyclopropane carboxylic acid        2-ethyl-amide; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provide a method of imaging atissue affected by an inflammation and/or infection in a subject in needthereof, comprising steps of:

(a) administering to the subject an effective amount of a labeledcompound of formula (VII)

or a pharmaceutically acceptable salt thereof, wherein:

-   -   one of Xa and Xb is O and the other is CH₂;    -   Y is CH₂ or S;    -   X₄ is hydrogen or halogen; and    -   X₂ is ¹²³I, ¹²⁴I, ¹²⁵I, or ¹³¹I; and    -   R is 2-ethanesulfonic acid isopropylamide, 2-ethanesulfonic acid        ethylamide, 2-ethanesulfonic acid methylamide, 2-ethanesulfonic        acid amide, 2-ethanesulfonic acid t-butylamide, 2-ethanesulfonic        acid isobutylamide, 2-ethanesulfonic acid cyclopropylamide,        isopropanesulfonic acid 2-ethylamide, ethanesulfonic acid        2-ethylamide, N-2 ethyl methanesulfonamide,        2-methyl-propane-2-sulfonic acid 2-ethyl amide,        2-methyl-propane-2-sulfinic acid 2-ethylamide,        2-methyl-propane-1-sulfonic acid 2-ethylamide,        cyclopropanesufonic acid 2-ethylamide, 3-propane-1-sulfonic acid        isopropylamide, 3-propane-1-sulfonic acid ethylamide,        3-propane-1-sulfonic acid methylamide, 3-propane-1-sulfonic acid        amide, 3-propane-1-sulfonic acid t-butylamide,        3-propane-1-sulfonic acid isobutylamide, 3-propane-1-sulfonic        acid cyclopropylamide, propane-2-sulfonic acid 3-propylamide,        ethanesulfonic acid 3-propylamide, N-3-propyl        methanesulfonamide, 2-methyl-propane-2-sulfonic acid        3-propylamide, 2-methyl-propane-2-sulfinic acid 3-propylamide,        2-methyl-propane-1-sulfonic acid 3-propylamide,        cyclopropanesulfonic acid 3-propylamide, 3-N-isopropyl        propionamide, 3-N-ethyl propionamide, 3-N-methyl propionamide,        3-propionamide, 3-N-t-butyl propionamide, 3-N-isobutyl        propionamide, 3-N-cyclopropyl propionamide, N-2-ethyl        isobutyramide, N-2-ethyl propionamide, N-2-ethyl acetamide,        N-2-ethyl formamide, N-2-ethyl 2,2-dimethyl-propionamide,        N-2-ethyl 3-methylbutyramide, or cyclopropane carboxylic acid        2-ethyl-amide; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method of imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

(a) administering to the subject an effective amount of a labeledcompound of formula VIII:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Xa-Xc-Xb is CH₂—CH₂—CH₂, CH═CH—CH₂, or CH₂—CH═CH;    -   Y is CH₂ or S;    -   X₂ is ¹²³I, ¹²⁴I, ¹²⁵I, or ¹³¹I; and    -   R is 2-ethanesulfonic acid isopropylamide, 2-ethanesulfonic acid        ethyl amide, 2-ethanesulfonic acid methylamide, 2-ethanesulfonic        acid amide, 2-ethanesulfonic acid t-butylamide, 2-ethanesulfonic        acid isobutylamide, 2-ethanesulfonic acid cyclopropylamide,        isopropanesulfonic acid 2-ethylamide, ethanesulfonic acid        2-ethylamide, N-2 ethyl methanesulfonamide,        2-methyl-propane-2-sulfonic acid 2-ethylamide,        2-methyl-propane-2-sulfinic acid 2-ethylamide,        2-methyl-propane-1-sulfonic acid 2-ethylamide,        cyclopropanesufonic acid 2-ethylamide, 3-propane-1-sulfonic acid        isopropylamide, 3-propane-1-sulfonic acid ethylamide,        3-propane-1-sulfonic acid methylamide, 3-propane-1-sulfonic acid        amide, 3-propane-1-sulfonic acid t-butylamide,        3-propane-1-sulfonic acid isobutylamide, 3-propane-1-sulfonic        acid cyclopropylamide, propane-2-sulfonic acid 3-propylamide,        ethanesulfonic acid 3-propylamide, N-3-propyl        methanesulfonamide, 2-methyl-propane-2-sulfonic acid        3-propylamide, 2-methyl-propane-2-sulfinic acid 3-propylamide,        2-methyl-propane-1-sulfonic acid 3-propylamide,        cyclopropanesulfonic acid 3-propylamide, 3-N-isopropyl        propionamide, 3-N-ethyl propionamide, 3-N-methyl propionamide,        3-propionamide, 3-N-t-butyl propionamide, 3-N-isobutyl        propionamide, 3-N-cyclopropyl propionamide, N-2-ethyl        isobutyramide, N-2-ethyl propionamide, N-2-ethyl acetamide,        N-2-ethyl formamide, N-2-ethyl 2,2-dimethyl-propionamide,        N-2-ethyl 3-methylbutyramide, or cyclopropane carboxylic acid        2-ethyl-amide; and

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method of imaginga tissue affected by an inflammation and/or infection in a subject inneed thereof, comprising steps of:

(a) administering to the subject an effective amount of a labeledcompound of formula IX:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X₃ is CH₂, CF₂, S, SO, SO₂, O, NH, or NR², wherein R² is alkyl;    -   X₂ is ¹²³I, ¹²⁴I, ¹²⁵I or ¹³¹I;    -   X₄ is hydrogen or halogen;    -   X₅ is O or CH₂;    -   R is 3-isopropylaminopropyl, 3-(isopropyl(methyl)amino)propyl,        3-(isopropyl(ethyl)amino)propyl,        3-((2-hydroxyethyl)(isopropyl)amino)propyl,        3-(methyl(prop-2-ynyl)amino)propyl,        3-(allyl(methyl)amino)propyl, 3-(ethyl(methyl)amino)propyl,        3-(cyclopropyl(propyl)amino)propyl,        3-(cyclohexyl(2-hydroxyethyl)amino)propyl,        3-(2-methylaziridin-1-yl)propyl, 3-(piperidin-1-yl)propyl,        3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 3-morpholinopropyl,        3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl,        2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl,        2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl,        2-(isobutyl(methyl)amino)ethyl, or        2-(methyl(prop-2-ynyl)amino)ethyl; and    -   n is 1 or 2;

(b) imaging the tissue by detecting the labeled compound in the subject.

In some embodiments, a compound of formula I binds to Hsp90. In someembodiments, a compound of formula 1 is an Hsp90 inhibitor. In someembodiments, a compound of formula II binds to Hsp90. In someembodiments, a compound of formula II is an Hsp90 inhibitor. In someembodiments, a compound of formula III binds to Hsp90. In someembodiments, a compound of formula III is an Hsp90 inhibitor. In someembodiments, a compound of formula IV binds to Hsp90. In someembodiments, a compound of formula IV is an Hsp90 inhibitor. In someembodiments, a compound of formula V binds to Hsp90. In someembodiments, a compound of formula V is an Hsp90 inhibitor. In someembodiments, a compound of formula VI binds to Hsp90. In someembodiments, a compound of formula VI is an Hsp90 inhibitor. In someembodiments, a compound of formula VII binds to Hsp90. In someembodiments, a compound of formula VII is an Hsp90 inhibitor. In someembodiments, a compound of formula VIII binds to Hsp90. In someembodiments, a compound of formula VIII is an Hsp90 inhibitor. In someembodiments, a compound of formula IX binds to Hsp90. In someembodiments, a compound of formula IX is an Hsp90 inhibitor.

Hsp90 may have multiple isoforms. In some embodiments, the labeledcompound binds to one or more isoforms of Hsp90. In some embodiments,the labeled compound binds to one or more isoforms of Hsp90 expressed ina tissue affected by an inflammation and/or infection. In someembodiments, the labeled compound binds to one form of Hsp90. In someembodiments, the labeled compound binds to more than one form of Hsp90.In some embodiments, the labeled compound binds to more than one form ofHsp90 with comparable affinity. In some embodiments, the labeledcompound binds to more than one form of Hsp90 with different affinity.

In some embodiments, Hsp90 is stress-specific Hsp90.

In some embodiments, a labeled compound binds to Hsp90 with a K_(D) ofless than about 1 mM, about 100 μM, about 10 μM or about 1 μM. In someembodiments, a labeled compound binds to Hsp90 with a K_(D) of less thanabout 1 mM. In some embodiments, a labeled compound binds to Hsp90 witha K_(D) of less than about 100 μM. In some embodiments, a labeledcompound binds to Hsp90 with a K_(D) of less than about 10 μM. In someembodiments, a labeled compound binds to Hsp90 with a K_(D) of less thanabout 1 μM.

In some embodiments, a labeled compound inhibits Hsp90. In someembodiments, a labeled compound has an IC₅₀ of less than about 1 mM,about 100 μM, about 10 μM, about 1 μM, about 100 nM, or about 10 nM. Insome embodiments, a labeled compound has an IC₅₀ of less than about 1mM. In some embodiments, a labeled compound has an IC₅₀ of less thanabout 100 μM. In some embodiments, a labeled compound has an IC₅₀ ofless than about 10 μM. In some embodiments, a labeled compound has anIC₅₀ of less than about 1 μM.

In some embodiments, a labeled compound that binds to Hsp90 has thestructure of formula I. In some embodiments, a labeled compound thatbinds to Hsp90 has the structure of formula II. In some embodiments, alabeled compound that binds to Hsp90 has the structure of formula III.In some embodiments, a labeled compound that binds to Hsp90 has thestructure of formula IV. In some embodiments, a labeled compound thatbinds to Hsp90 has the structure of formula V. In some embodiments, alabeled compound that binds to Hsp90 has the structure of formula VI. Insome embodiments, a labeled compound that binds to Hsp90 has thestructure of formula VII. In some embodiments, a labeled compound thatbinds to Hsp90 has the structure of formula VIII. In some embodiments, alabeled compound that binds to Hsp90 has the structure of formula IX.

Exemplary assays for measuring binding and/or inhibition of Hsp90 arewidely known in the art, for example but not limited to those describedin U.S. Pat. No. 7,834,181 and its cited references thereof, theentirety of each of which is hereby incorporated by reference.

Suitable imaging technologies are widely known and practiced in the art.In some embodiments, the imaging process in step (b) of a providedmethod comprises tomography. In some embodiments, the imaging processcomprises positron emission tomography (PET). In some embodiments, theimaging process comprises single-photon emission computed tomography(SPECT). In some embodiments, the imaging process comprises more thanone technique. In some embodiments, the imaging process comprises PETcombined with another imaging technique. In some embodiments, PET iscombined with X-ray Computed Tomography (CT), Magnetic Resonance Imaging(MRI) or single-photon emission computed tomography (SPECT). In someembodiments, the imaging process comprises PET-CT. In some embodiments,the imaging process comprises PET-MRI. In some embodiments, the imagingprocess comprises PET-SPECT.

In some embodiments, a provided method further comprises collectingelectrocardiography (ECG) data. ECG data can be collected prior to,concurrent with, and/or subsequent to the imaging process. In someembodiments, ECG data, among other purposes, are used to solve imagingproblems caused by heart motion. ECG-gated imaging is widely known andpracticed in the art to improve imaging results including resolution.

In some embodiments, imaging is performed at one time point. In someembodiments, imaging is performed at more than one time point. In someembodiments, imaging is performed at about 0 min, 5 min, 10 min, 15 min,20 min, 25 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 6 hours, 12hours, 24 hours, 36 hours, 48 hours, 60 hours, 72 hours, 5 days, 6 days,1 week post-administration of a labeled compound. In some embodiments,imaging is performed at about 0-30 minutes post-administration of alabeled compound. In some embodiments, imaging is performed at about10-60 minutes post-administration of a labeled compound. In someembodiments, imaging is performed at about 10 min-3 hourspost-administration of a labeled compound. In some embodiments, imagingis performed at about 10 min-6 hours post-administration of a labeledcompound. In some embodiments, imaging is performed at about 10 min toabout 12 hours post-administration of a labeled compound. In someembodiments, imaging is performed at about 10 min to about 24 hourspost-administration of a labeled compound. In some embodiments, imagingis performed at about 10 min to about 36 hours post-administration of alabeled compound. In some embodiments, imaging is performed at about 10min to about 48 hours post-administration of a labeled compound. In someembodiments, imaging is performed at about 10 min to about 72 hourspost-administration of a labeled compound. In some embodiments, imagingis performed after about 72 hours post-administration of a labeledcompound.

In certain embodiments, imaging of provided methods is performed bydetecting a labeled compound in various tissues in a subject that can beaffected by an inflammation and/or infection. Any tissue or organsubject to inflammation and/or infection may be so imaged using themethods provided herein. In some embodiments, detecting the labeledcompound in the subject comprises measuring signal intensity from thelung of the subject. In some embodiments, detecting the labeled compoundin the subject comprises measuring signal intensity from the colon ofthe subject. In some embodiments, detecting the labeled compound in thesubject comprises measuring signal intensity from the skin of thesubject. In some embodiments, detecting the labeled compound in thesubject comprises measuring signal intensity from the macrophages of thesubject. In some embodiments, detecting the labeled compound in thesubject comprises measuring signal intensity from the stroma of thesubject. In some embodiments, detecting the labeled compound in thesubject comprises measuring signal intensity from the cardiac tissue ofthe subject.

In some embodiments, a provided method further comprises a step ofcomparing an image from step (b) to a reference. In some embodiments, areference is the image of healthy tissue within the image. In someembodiments, a reference is an image taken at a different time point forthe same subject. In some embodiments, a reference is an average image,wherein the data for each point of the image are the average of the datafor that point in two or more images that are averaged. In someembodiments, a reference is an image taken without an inflammationand/or infection present. In some embodiments, a reference is the“average” image of a patient population. In some embodiments, areference is the average image of a healthy population. In someembodiments, a reference is the average image of a population with aninflammation and/or infection. In some embodiments, an average image isconstructed by averaging the signal intensity of each subject in apopulation for every position of the image. In some embodiments, areference image is what a trained physician or radiologist knows to be anormal or average image for the tissue being imaged.

In some embodiments, a provided method further comprises a step thatincludes comparing the data of a first tissue position of an imageobtained in step (b) to those of a second tissue position, wherein thesecond tissue position is from another image or a different tissueposition of the same image. In some embodiments, a provided methodfurther comprises a step that includes comparing the data of a firsttissue position of an image obtained in step (b) to those of a secondtissue position, wherein the second tissue position is from anotherimage. In some embodiments, a provided method further comprises a stepthat includes comparing the data of a first tissue position of an imageobtained in step (b) to those of a second tissue position, wherein thesecond tissue position is a different position of the same image. Insome embodiments, the comparison is a direct comparison. In someembodiments, the comparison is an indirect comparison. In someembodiments, the comparison is an indirect comparison, wherein at leastone of the first and second positions is compared to a reference. Insome embodiments, a reference is from an average tissue image.

Unless otherwise specified, “imaging” refers to a process of collectingdata using a medical imaging device, and an “image” refers to a set ofcollected data. The set of collected data can be collected, transmitted,stored, processed, analyzed or presented in various formats, includingbut not limited to visual pictures.

Measuring of signal intensity in images produced from various medicaltechniques is a standard practice known by a person of ordinary skill inthe art. In some embodiments, computer software, sometimes commerciallyavailable and/or installed with an imaging instrumentation system, isused to analyze signals collected by an imaging system, includingquantitative and qualitative comparison with a reference point and/or areference image. In some embodiments, a lack of signal, or decreasedintensity of signal, when compared to one or more reference pointsand/or one or more reference images, indicates relatively lessinflammation and/or infection in the location that lacks the signal orhas decreased intensity of signal. A physician, upon analyzing andinterpreting these results, can then make the medically relevantdescisions and recommendations on proper treatment.

In some embodiments, Hsp90 is upregulated in areas of inflammations andinfections. Therefore, without wishing to be bound by any particulartheory, it is believed that an increase in signal could be realized insuch instances where a labeled Hsp90 inhibitor is used, particularly onethat selectively binds stress-specific Hsp90.

In some embodiments, an inflammation and/or infection is associated withHsp90. In some embodiments, an inflammation and/or infection isassociated with stress-specific Hsp90. In some other embodiments, aninflammation and/or infection is not associated with Hsp90. In someembodiments, a provided tissue imaging method is performed for thediagnosis, treatment, prevention or monitoring of a disease, disorder,or condition on a subject irrespective of the role of Hsp90 in the saiddisease, disorder, or condition.

In some embodiments, a labeled compound is co-administered with anon-radioactive therapeutic compound. In some embodiments, a labeledcompound has the same structure as the non-radioactive therapeuticcompound but is labeled by the enrichment of one or more radioactiveisotopes of one or more elements. In some embodiments, a labeledcompound is administered concurrently with a non-labeled compound. Insome embodiments, a labeled compound is administered prior to anon-labeled compound. In some embodiments, a labeled compound isadministered subsequent to a non-labeled compound. In some embodiments,concurrent administration uses a formulation comprising a mixture oflabeled compound and non-radioactive compound. In some embodiments, alabeled and non-radioactive therapeutic compound are co-administered butvia different routes and/or sites of administration. In someembodiments, a non-labeled compound is an Hsp90 inhibitor.

In some embodiments, imaging of a labeled compound, among other things,provides information on the distribution of the co-administeredtherapeutic compound in tissues affected by an inflammation and/orinfection. In some embodiments, imaging measures the accessibility ofHsp90 in the tissue affected by an inflammation and/or infection to atherapeutic compound. In some embodiments, imaging measures theconcentrations of a labeled and/or non-labeled therapeutic compound inthe tissue affected by an inflammation and/or infection. In someembodiments, imaging measures the concentration of non-labeledtherapeutic compound by use of a radiotracer amount of labeled compound.In some embodiments, imaging measures tissue concentrations ofradioactivity for labeled-compound administered at a therapeuticallyeffective amount. In some embodiments, imaging measures the occupancy orsaturation of Hsp90 achieved by a therapeutic compound in the tissueaffected by an inflammation and/or infection. In some embodiments,imaging measures the ability of a therapeutic compound to displace thelabeled compound in the tissue affected by an inflammation and/orinfection.

The radioactive isotopes of radiolabeled compounds decay with time. Asknown by a person having ordinary skill in the art, for differentpurposes radiolabeled compounds with different half-life can be used. Insome embodiments, a radioactive label or a radiolabeled compound has ahalf-life of at least about 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 18, 24, 36, 48, 72, 96, or 100.3 hours. In some embodiments,a radioactive label or a radiolabeled compound has a half-life of atleast about 1 hour. In some embodiments, a radioactive label or aradiolabeled compound has a half-life of at least about 2 hours. In someembodiments, a radioactive label or a radiolabeled compound has ahalf-life of at least about 3 hours. In some embodiments, a radioactivelabel or a radiolabeled compound has a half-life of at least about 4hours. In some embodiments, a radioactive label or a radiolabeledcompound has a half-life of at least about 5 hours. In some embodiments,a radioactive label or a radiolabeled compound has a half-life of atleast about 6 hours. In some embodiments, a radioactive label or aradiolabeled compound has a half-life of at least about 7 hours. In someembodiments, a radioactive label or a radiolabeled compound has ahalf-life of at least about 8 hours. In some embodiments, a radioactivelabel or a radiolabeled compound has a half-life of at least about 9hours. In some embodiments, a radioactive label or a radiolabeledcompound has a half-life of at least about 10 hours. In someembodiments, a radioactive label or a radiolabeled compound has ahalf-life of at least about 11 hours. In some embodiments, a radioactivelabel or a radiolabeled compound has a half-life of at least about 12hours. In some embodiments, a radioactive label or a radiolabeledcompound has a half-life of at least about 18 hours. In someembodiments, a radioactive label or a radiolabeled compound has ahalf-life of at least about 24 hours. In some embodiments, a radioactivelabel or a radiolabeled compound has a half-life of at least about 36hours. In some embodiments, a radioactive label or a radiolabeledcompound has a half-life of at least about 48 hours. In someembodiments, a radioactive label or a radiolabeled compound has ahalf-life of at least about 72 hours. In some embodiments, a radioactivelabel or a radiolabeled compound has a half-life of at least about 96hours. In some embodiments, a radioactive label or a radiolabeledcompound has a half-life of about 59.4 days. In some embodiments, aradioactive label or a radiolabeled compound has a half-life of about8.0 days. In some embodiments, a radioactive label or a radiolabeledcompound has a half-life of about 60 days. In some embodiments, aradiolabelled compound comprises radioactive labels having differenthalf-lives.

It will be appreciated that the comparison of images taken at differenttime points, including but not limited to before and after aninflammation and/or infection, are useful in the diagnosis or treatmentof the inflammation and/or infection. In some embodiments, an imagebefore an inflammation and/or infection is used as a reference image, towhich another image is compared. In some embodiments, a second image ofa tissue affected by an inflammation and/or infection is collected aftera first image of the tissue is collected. In some embodiments, aprovided method comprises a step of comparing a second image to a firstimage. In some embodiments, a provided method comprises a step ofcomparing a second image to a first image, comprising normalizing thesignal intensity of each region of the second image to the first image.In some embodiments, a provided method comprises a step of comparing asecond image to a first image, comprising normalizing the signalintensity of each region of the second image relative to the firstimage, wherein weaker normalized signal intensity indicates presence ofless Hsp90. In some embodiments, weaker normalized signal indicatespresence of less stress-specific Hsp90. In some embodiments, weakernormalized signal indicates improvement of an inflammation and/orinfection. In some embodiments, weaker normalized signal indicates thatan existing treatment ameliorates an inflammation and/or infection.

In some embodiments, the present invention provides a method for thediagnosis of an inflammation and/or infection in a tissue, comprisingadministering a labeled compound of any of formula I to IX to a subjectin need thereof, and imaging the tissue by detecting the labeledcompound in the subject. In some embodiments, the disease or conditionis psoriasis. In some embodiments, an inflammation and/or infection isassociated with abnormal Hsp90 expression or protein levels in a tissue.In some embodiments, an inflammation and/or infection is abnormal Hsp90expression or protein levels in an tissue. In some embodiments, abnormalHsp90 expression or protein levels in a tissue affected by aninflammation and/or infection are higher than the expression or levelsin a normal healthy tissue. In some embodiments, abnormal Hsp90expression or protein level in a tissue affected by an inflammationand/or infection is lower than the expression or levels in a normalhealthy tissue. In some embodiments, an abnormal Hsp90 expression orprotein level in a tissue affected by an inflammation and/or infectioncomprises Hsp90 isoforms in ratios different than a normal healthytissue.

In some embodiments, the present invention provides a method for thetreatment of a tissue affected by, or prevention of an tissue from, aninflammation and/or infection, comprising administering a labeledcompound of any of formula I to IX to a subject in need thereof, andimaging the tissue by detecting the labeled compound in the subject.

In some embodiments, the present invention provides a method formonitoring the effect of an inflammation and/or infection treatment in asubject in need thereof; comprising steps of:

(a) administering a labeled compound of any of formula I to IX to thesubject who is scheduled for the inflammation and/or infectiontreatment, currently undergoing the inflammation and/or infectiontreatment, or has completed or discontinued the inflammation and/orinfection treatment;(b) imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound; and(c) recommending to the subject an appropriate avoidance, continuation,modification, or termination in the inflammation and/or infectiontreatment.

In some embodiments, a treatment described herein includes, but is notlimited to, use of an anti-inflammatory drug or anti-infective drug, asdescribed herein.

In some embodiments, the present invention provides a method formonitoring an inflammation and/or infection treatment regimen,comprising steps of:

(a) administering a labeled compound of any of formula I to IX to asubject under the inflammation and/or infection treatment regimen;(b) imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound in the subject;(c) analyzing the images from step (b); and(d) maintaining, modifying, or discontinuing the inflammation and/orinfection treatment regimen.

Patient stratification is important for clinical trials, preventativemedicine, and treatment. In some embodiments, the present inventionprovides methods for patient stratification based on inflammation and/orinfection imaging. In some embodiments, the present invention provides amethod for selecting subjects for an inflammation and/or infectiontreatment, comprising steps of:

-   -   (a) administering a labeled compound of any of formula I to IX        to a subject;    -   (b) imaging a tissue affected by the inflammation and/or        infection by detecting the labeled compound in the subject;    -   (c) analyzing the images from step (b); and    -   (d) including or excluding the subject for the treatment.

In some embodiments, the presence of a labeled compound in a tissueindicates the presence of inflammation and/or infection, and to includethe subject for the treatment. In some embodiments, abnormal signalcompared to a reference, as provided herein, indicates affection by aninflammation and/or infection, and to include the subject for thetreatment. The abnormal signal can be increased or decreased compared toa reference, as provided herein. In some embodiments, the absence of alabeled compound in a tissue indicates no inflammation and/or infectionis present, and to exclude the subject for the treatment.

In some embodiments, a treatment comprises the use of a compound thatbinds to Hsp90. In some embodiments, a treatment comprises the use of anHsp90 inhibitor, also referred to as a “Hsp90 inhibition therapy” or“Hsp90 therapy”. In some embodiments, the method for selecting a subjectis for a clinical trial. In some embodiments, the method for selecting asubject is for a clinical trial of a new therapy or diagnosis. In someembodiments, the method for selecting a subject is for a clinical trialof a new therapy or diagnosis for an inflammation and/or infection.

In some embodiments, a provided method provides an approach to patientscreening, distinguishing patients likely to have either a favorable orunfavorable therapeutic response to a compound that binds to Hsp90 foran inflammation and/or infection treatment. In some embodiments, aprovided method provides an approach to patient screening,distinguishing patients likely to have either a favorable or unfavorabletherapeutic response to a compound for an inflammation and/or infectiontreatment, wherein the compound is an unlabeled counterpart of acompound of any of formula I to IX.

In some embodiments, the present invention provides a method for thetreatment of a tissue affected by, or prevention of a tissue from, aninflammation and/or infection, comprising the step of administering acompound of any of formula I to IX to a subject in need thereof.

In some embodiments, the present invention provides a method forselecting subjects for an inflammation and/or infection treatment,comprising steps of:

-   -   (a) administering to a subject a labeled compound that binds to        stress-specific Hsp90; and    -   (b) imaging a tissue affected by the inflammation and/or        infection by detecting the labeled compound in the subject;        wherein increased uptake of the labeled compound indicates more        likelihood for the subject to benefit from the treatment.

In some embodiments, an inflammation and/or infection treatmentcomprises the use of a compound that binds to Hsp90. In someembodiments, an inflammation and/or infection treatment comprises theuse of a compound that binds to stress-specific Hsp90. In someembodiments, an inflammation and/or infection treatment comprises theuse of the non-labeled counterpart of a labeled compound describedherein.

Dosing is often a key aspect of a treatment regimen. In someembodiments, the present invention provides a method for optimizing thedosage of a drug based on imaging, so that the desired therapeuticeffects can be achieved with minimal side effects. In some embodiments,the present invention provides a method for determining the dosage of adrug for the treatment of an inflammation and/or infection, comprisingsteps of:

-   -   (a) administering a labeled compound of any of formula I to IX        to a subject;    -   (b) imaging a tissue affected by the inflammation and/or        infection by detecting the labeled compound in the subject;    -   (c) analyzing the images from step (b); and    -   (d) administering to the subject a suitable amount of the drug.

In some embodiments, a provided method comprises determining theeffective dosage of a drug. In some embodiments, a provided methodcomprises determining the toxicity of a drug in the subject. In someembodiments, a provided method comprises determining the minimumeffective dosage of a drug. In some embodiments, a provided methodcomprises determining the highest toxicity dosage for a subject. In someembodiments, a provided method comprises determining the highesttolerable dosage for a subject. In some embodiments, a provided methodcomprises determining the balance between efficacy and toxicity and/orsafety.

In some embodiments, a provided method further comprises administering anon radioactive therapeutic amount of a compound that binds to Hsp90. Insome embodiments, analyzing the images in provided methods is done withcomparison to images obtained when administering only the labeledcompound. In some embodiments, the labeled compound is administeredbefore, during, or after administration of a non-radioactive therapeuticcompound.

In some embodiments, the imaging of a provided method is non-invasive.

In some embodiments, a provided method comprises identifying abnormalsignal compared to a reference, wherein the abnormal signal indicates aninflammation and/or infection in the tissue. In some embodiments, anincreased signal (e.g., a “hot spot”) indicates an inflammation and/orinfection in the tissue. In some embodiments, a decreased signal (e.g.,a “cold spot”) indicates inflammation and/or infection in the tissue. Itwill be appreciated that in such instances, “hot” or “cold” is relativeto the amount of labeled compound that normally accumulates insurrounding healthy tissue. Without wishing to be bound by any theory,local destruction of living tissue by an inflammation and/or infectionmay cause less Hsp 90 targeted binding, resulting in decreased signalsas compared to the reference, e.g., surrounding healthy tissues in theorgan. As such, in certain embodiments, a decreased signal or “coldspot” indicates an inflammation and/or infection in the tissue. Theskilled artisan will be familiar with the relevant context and be ableto ascertain whether an increased or decreased signal (i.e., contrast insignal relative to surrounding or normal tissue) is indicative of aninflammation or infection. Also without wishing to be bound by anytheory, in some embodiments, tissues (e.g., the liver) are known toaccumulate metabolites of Hsp90 inhibitors, and may therefore manifestas locales of apparent high uptake when in fact the signal is notrepresentative of compound bound to Hsp90. Such embodiments are known tothe skilled artisan and are to be taken into account when assessing therelative signal of “hot” or “cold” spots near or within such tissues.

In some embodiments, a provided method comprises identifying decreasedsignal compared to a reference, wherein the decreased signal indicatesamelioration of an inflammation and/or infection in the tissue. In someembodiments, the decreased signal is preceded by a period of increasedsignal compared to a reference, for example a “flare response” wherelabeled compound uptake in a tissue increases after treatment, thenlater subsides. The period of increased signal can be 0.5 hr, 1 hr, 2hrs, 3 hrs, 4 hrs, 5 hrs, 6 hrs, 7 hrs, 8 hrs, 9 hrs, 10 hrs, 12 hrs, 15hrs, 18 hrs, 21 hrs, or 24 hrs or more after commencing treatment.

In some embodiments, a subject in a provided method is a cancer patient.

Exemplary Drugs, Including Non-Hsp90 Targeting Drugs

In some embodiments, a drug used in provided methods is ananti-inflammatory drug. Exemplary anti-inflammatory drugs are well knownand prescribed in the art. In some embodiments, drugs can be activeagents used conventionally for immunosuppression or for inflammatoryconditions, allergic disorders, or immune disorders, which include, butare not limited to, steroids, non-steroidal anti-inflammatory agents,antihistamines, analgesics, immunosuppressive agents, and suitablemixtures thereof.

Exemplary non-steroidal anti-inflammatory agents include, but are notlimited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen,flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen,aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin,sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin,fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid,flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal,piroxicam, sudoxicam, isoxicam; salicylic acid derivatives, includingaspirin, sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phcnacetin;indolc and indene acetic acids, including indomethacin, sulindac, andctodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone and pharmaceutically acceptablesalts thereof and mixtures thereof. For additional description of theNSAIDs, see Paul A. Insel, Analgesic-Antipyretic and AntiinflammatoryAgents and Drugs Employed in the Treatment of Gout, in Goodman &Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B.Molinhoff and Raymond W. Ruddon eds., 9.sup.th ed 1996) and Glen R.Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington:The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed.19th ed. 1995) which are hereby incorporated by reference in theirentireties.

Exemplary antihistamines include, but are not limited to, loratadine,cetirizine, fexofenadine, desloratadine, diphenhydramine,chlorpheniramine, chlorcyclizine, pyrilamine, promethazine, terfenadine,doxepin, carbinoxamine, clemastine, tripelennamine, brompheniramine,hydroxyzine, cyclizine, meclizine, cyproheptadine, phenindamine,acrivastine, azelastine, levocabastine, and mixtures thereof. Foradditional description of anthihistamines, see Goodman & Gilman's ThePharmacological Basis of Therapeutics (2001) 651-57, 10.sup.th ed).

Exemplary immunosuppressive agents include, but are not limited to,glucocorticoids, corticosteroids (such as Prednisone or Solumedrol), Tcell blockers (such as cyclosporin A and FK506), purine analogs (such asazathioprine (Imuran)), pyrimidine analogs (such as cytosinearabinosidc), alkylating agents (such as nitrogen mustard, phenylalanincmustard, busifan, and cyclophosphamide), folic acid antagonists (such asaminopterin and methotrexate), macrolides (such as rapamycin),antibiotics (such as actinomycin D, mitomycin C, puramycin, andchloramphenicol), human IgG, antilymphocyte globulin (ALG), andantibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5,anti-CD7, anti-IL-2 receptor, anti-alpha/beta TCR, anti-ICAM-1,anti-CD20 (Rituxan), anti-IL-12 and antibodies to immunotoxins).

In some embodiments, a drug is an anti-infective drug. Exemplaryanti-infective drugs are well known and prescribed in the art.

In some embodiments, a drug is an anti-viral agent. Nonlimiting examplesof anti viral agents are protease inhibitors (e.g., nafamostat,camostat, gabexate, epsilon-aminocapronic acid and aprotinin), fusioninhibitors (e.g., BMY-27709, CL 61917, and CL 62554), M2 proton channelblockers (e.g., Amantadine and Rimantadine), polymerase inhibitors(e.g., 2-deoxy-2′fluoroguanosides (2′-fluoroGuo),6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705),T-705-4-ribofuranosyl-5′-triphosphate (T-705RTP)), endonucleaseinhibitors (e.g., L-735,822 and flutimide), kinase inhibitors (e.g.,U0126 (a MEK inhibitor), PD098059 (a MEK-specific inhibitor),PD-184352/CI-1040 (a MEK inhibitor), PD 0325901 (a MEK inhibitor),ARRY-142886/AZD-6244 (a MEK1 and MEK2 inhibitor)), neuraminidaseinhibitors (e.g., Zanamivir (Relenza), Oseltamivir (Tamiflu), Peramivirand ABT-675 (A-315675)), all of which are described in Hsieh et al.,Current Pharmaceutical Design, 2007, 13, 3531-3542. Other examples ofantiviral drugs include, but are not limited to, reverse transcriptaseinhibitor (e.g., Abacavir, Adefovir, Delavirdine, Didanosine, Efavirenz,Emtricitabine, Lamivudine, Nevirapine, Stavudine, Tenofovir, Tenofovirdisoproxil, and Zalcitabine) Aciclovir, Acyclovir, protease inhibitor(e.g., Amprenavir, lndinavir, Nelfinavir, Ritonavir, and Saquinavir),Arbidol, Atazanavir, Atripla, Boceprevir, Cidofovir, Combivir,Darunavir, Docosanol, Edoxudine, entry inhibitors (e.g., Enfuvirtide andMaraviroc), Entecavir, Famciclovir, Fomivirsen, Fosamprenavir,Foscarnet, Fosfonet, Ganciclovir, Ibacitabine, Immunovir, Idoxuridine,Imiquimod, Inosine, integrase inhibitor (e.g., Raltegravir), interferons(e.g., types I, II, and III), Lopinavir, Loviride, Moroxydine, Nexavir,nucleoside analogues (e.g., Aciclovir), Penciclovir, Pleconaril,Podophyllotoxin, Ribavirin, Tipranavir, Trifluridine, Trizivir,Tromantadine, Truvada, Valaciclovir (Valtrex), Valganciclovir,Vicriviroc, Vidarabine, Viramidine, and Zidovudine.

In some embodiments, a drug is an anti-fungal agent. Nonlimitinganti-fungal agents are imidazoles, FK 463, amphotericin B. BAY 38-9502,MK 991, pradimicin, UK 292, butenafine, chitinase, 501 cream,Acrisorcin; Ambruticin; Amorolfine, Amphotericin B; Azaconazole;Azaserine; Basifungin; Bifonazole; Biphenamine Hydrochloride;Bispyrithione Magsulfex; Butoconazole Nitrate; Calcium Undecylenate;Candicidin; Carbol-Fuchsin; Chlordantoin; Ciclopirox; CiclopiroxOlamine; Cilofungin; Cisconazole; Clotrimazole; Cuprimyxin; Denofungin;Dipyrithione; Doconazole; Econazole; Econazole Nitrate; Enilconazole;Ethonam Nitrate; Fenticonazole Nitrate; Filipin; Fluconazole;Flucytosine; Fungimycin; Griseofulvin; Hamycin; Isoconazole;Itraconazole; Kalafungin; Ketoconazole; Lomofungin; Lydimycin;Mcpartricin; Miconazolc; Miconazolc Nitrate; Moncnsin; Moncnsin Sodium;Naftifine Hydrochloride; Neomycin Undecylenate; Nifuratel; Nifurmerone;Nitralamine Hydrochloride; Nystatin; Octanoic Acid; Orconazole Nitrate;Oxiconazole Nitrate; Oxifungin Hydrochloride; Parconazole Hydrochloride;Partricin; Potassium Iodide; Proclonol; Pyrithione Zinc; Pyrrolnitrin;Rutamycin; Sanguinarium Chloride; Saperconazole; Scopafungin; SeleniumSulfide; Sinefungin; Sulconazole Nitrate; Terbinafine; Terconazole;Thiram; Ticlatone; Tioconazole; Tolciclate; Tolindate; Tolnaftate;Triacetin; Triafungin; Undecylenic Acid; Viridofulvin; ZincUndecylenate; and Zinoconazole Hydrochloride.

In some embodiments, a drug is an antibacterial agent. In someembodiments, antibacterial agents are antibiotics of the beta-lactamgroup such as natural penicillins, semisynthetic penicillins, naturalcephalosporins, semisynthetic cephalosporins, cephamycins, 1-oxacephems,clavulanic acids, penems, carbapenems, nocardicins, monobactams;tetracyclines, anhydrotetracyclines, anthracyclines; aminoglycosides;nucleosides such as N-nucleosides, C-nucleosides, carbocyclicnucleosides, blasticidin S; macrolides such as 12-membered ringmacrolides, 14-membered ring macrolides, 16-membered ring macrolides;ansamycins; peptides such as bleomycins, gramicidins, polymyxins,bacitracins, large ring peptide antibiotics containing lactone linkages,actinomycins, amphomycin, capreomycin, distamycin, enduracidins,mikamycin, neocarzinostatin, stendomycin, viomycin, virginiamycin;cycloheximide; cycloserine; variotin; sarkomycin A; novobiocin;griseofulvin; chloramphenicol; mitomycins; fumagillin; monensins;pyrrolnitrin; fosfomycin; fusidic acid; D-(p-hydroxyphenyl)glycine;D-phenylglycine; or enediynes.

In some embodiments, a drug is an antibiotic selected frombenzylpenicillin (potassium, procaine, benzathine),phenoxymethylpenicillin (potassium), phenethicillin potassium,propicillin, carbenicillin (disodium, phenyl sodium, indanyl sodium),sulbenicillin, ticarcillin disodium, methicillin sodium, oxacillinsodium, cloxacillin sodium, dicloxacillin, flucloxacillin, ampicillin,mezlocillin, piperacillin sodium, amoxicillin, ciclacillin, hectacillin,sulbactam sodium, talampicillin hydrochloride, bacampicillinhydrochloride, pivmecillinam, cephalexin, cefaclor, cephaloglycin,cefadroxil, cephradine, cefroxadine, cephapirin sodium, cephalothinsodium, cephacetrile sodium, cefsulodin sodium, cephaloridine,cefatrizine, cefoperazone sodium, cefamandole, vefotiam hydrochloride,cefazolin sodium, ceftizoxime sodium, cefotaxime sodium, cefmenoximehydrochloride, cefuroxime, ceftriaxone sodium, ceftazidime, cefoxitin,cefmetazole, cefotetan, latamoxef, clavulanic acid, imipenem, aztreonam,tetracycline, chlortetracycline hydrochloride,demethylchlortetracycline, oxytetracycline, methacycline, doxycycline,rolitetracycline, minocycline, daunorubicin hydrochloride, doxorubicin,aclarubicin, kanamycin sulfate, bekanamycin, tobramycin, gentamycinsulfate, dibekacin, amikacin, micronomicin, ribostamycin, neomycinsulfate, paromomycin sulfate, streptomycin sulfate, dihydrostreptomycin,destomycin A, hygromycin B, apramycin, sisomicin, netilmicin sulfate,spectinomycin hydrochloride, astromicin sulfate, validamycin,kasugamycin, polyoxin, blasticidin S, erythromycin, erythromycinestolate, oleandomycin phosphate, tracetyloleandomycin, kitasamycin,josamycin, spiramycin, tylosin, iveiuiectin, midecamycin, bleomycinsulfate, peplomycin sulfate, gramicidin S, polymyxin B, bacitracin,colistin sulfate, colistinmethanesulfonate sodium, enramycin, mikamycin,virginiamycin, capreomycin sulfate, viomycin, enviomycin, vancomycin,actinomycin D, neocarzinostatin, bestatin, pepstatin, monensin,lasalocid, salinomycin, amphotericin B, nystatin, natamycin,trichomycin, mithramycin, lincomycin, clindamycin, clindamycin palmitatehydrochloride, flavophospholipol, cycloserine, pecilocin, griseofulvin,chloramphenicol, chloramphenicol palmitate, mitomycin C, pyrrolnitrin,fosfomycin, fusidic acid, bicozamycin, tiamulin, or siccanin.

In some embodiments, a drug is an anti-parasitic agent. Nonlimitingexamples of anti-parasitic agents are albendazole, amphotericin B,benznidazole, bithionol, chloroquine HCl, chloroquine phosphate,clindamycin, dehydroemetine, diethylcarbamazine, diloxanide furoate,eflornithine, furazolidaone, glucocorticoids, halofantrine, iodoquinol,ivermectin, mebendazole, mefloquinc, mcgluminc antimoniatc, mclarsoprol,metrifonate, mctronidazolc, niclosamidc, nifurtimox, oxamniquine,paromomycin, pentamidine isethionate, piperazine, praziquantel,primaquine phosphate, proguanil, pyrantel pamoate,pyrimethanmine-sulfonamides, pyrimethanmine-sulfadoxine, quinacrine HCl,quinine sulfate, quinidine gluconate, spiramycin, stibogluconate sodium(sodium antimony gluconate), suramin, tetracycline, doxycycline,thiabendazole, tinidazole, trimethroprim-sulfamethoxazole, andtryparsamide.

In some embodiments, a drug is a compound having the structure offormula X wherein each variable is independently as described in classesand subclasses herein, both singly and in combination.

Non-Radioactive Therapeutic Compounds

In some embodiments, provided methods use a non-radioactive therapeuticcompound alone or in combination with the exemplary drugs named above.

In some embodiments, the non-radioactive therapeutic compound used in aprovided method binds to Hsp90. In some embodiments, the non-radioactivetherapeutic compound is an Hsp90 inhibitor. In some embodiments, thenon-radioactive compound is a natural product or its derivatives. Insome embodiments, the non-radioactive compound is Geldanamycin or itsderivative. In some embodiments, the non-radioactive compound isradicicol or its derivative. In some embodiments, the non-radioactivecompound is Gamitrinib or its derivative.

In some embodiments, the non-radioactive compound has the structure offormula X:

-   -   or its pharmaceutically acceptable salt thereof, wherein:    -   each Y is independently CH or N;    -   R is hydrogen, a C₁ to C₁₀ alkyl, alkenyl, alkynyl, or an        alkoxyalkyl group, optionally comprising one or more        heteroatoms, or a targeting moiety connected to N9 via a linker;        -   X₄ is hydrogen or halogen;        -   X₃ is CH₂, CF₂, 5, SO, SO₂, O, NH, or NR², wherein R² is            alkyl;        -   X₂ is halogen, alkyl, alkoxy, halogenated alkoxy,            hydroxyalkyl, pyrollyl, optionally substituted aryloxy,            alkylamino, dialkylamino, carbamyl, amido, alkylamido,            dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy,            trihalocarbon, thioalkyl, C(O)O-alkyl, NH₂, OH, CN, SO₂X₅,            NO₂, NO, C(S)R, NHSO₂X₅, or C(O)R, where X₅ is F, NH₂,            alkyl, or H, and R₂ is alkyl, NH₂, NH-alkyl, or O-alkyl; and        -   X₁ represents two substituents, which may be the same or            different, disposed in the 4′ and 5′ positions on the aryl            group, wherein X₁ is selected from halogen, alkyl, alkoxy,            halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally            substituted aryloxy, alkylamino, dialkylamino, carbamyl,            amido, alkylamido, dialkylamido, acylamino,            alkylsulfonylamido, trihalomethoxy, trihalocarbon,            thioalkyl, COO-alkyl, NH₂OH, CN, SO₂X₅, NO₂, NO, C(S)R,            NHSO₂X₅, or C(O)R, where X₅ is F, NH₂, alkyl, or H, and R²            is alkyl, NH₂, NH-alkyl, or O-alkyl, C₁ to C₆ alkyl or            alkoxy, or wherein X₁ has the formula —O—(CH₂)_(n)O—,            wherein n is an integer from 1 to 2, and one of the oxygens            is bonded at the 5′-position and the other at the            4′-position of the aryl ring.

In some embodiments, the non-radioactive compound is a non-radioactivecounterpart of a compound having the structure of any of formula III toIX.

In some embodiments, the non-radioactive therapeutic compound iscompound A:

Labeled Compounds

In some embodiments, a labeled compound is a labeled compound of formula1, wherein the prior-labeling compound has the structure of formula 1.In some embodiments, a labeled compound that binds to Hsp90 is a labeledcompound of formula I. In some embodiments, the labeled compound thatbinds to Hsp90 has the structure of any one of formula II to IX. In someembodiments, the labeled compound that binds to Hsp90 is a labelednatural product or its derivative. In some embodiments, the labeledcompound is labeled Geldanamycin or its derivative. In some embodiments,the labeled compound is labeled radicicol or its derivative. In someembodiments, the labeled compound is labeled Gamitrinib or itsderivative. Exemplary non-labeled compounds that bind to Hsp90 and maybe labeled are widely known in the art, including but not limited tothose described in Jhaveri and Modi, HSP90 inhibitors for cancer therapyand overcoming drug resistance, Adv Pharmacol. 2012; 65:471-517; andTaldone et al, Design, synthesis, and evaluation of small molecule Hsp90probes, Bioorg Med Chem. 2011; 19(8):2603-14; U.S. Pat. Nos. 8,178,687and 8,324,240; United States Patent Application Publication Nos.US2012/0277257, US2012/0264770, US2012/0237508, US2013/0045983,US2005/0107343, US2008/0234314, and US2012/0046266; and PCT patentapplication publication WO2008/115719, WO2008/118391, WO2004/097428,WO2006/098761, WO2006/123165, WO2007/134677, WO2008/093075,WO2007/104944, WO2009/097578, WO2008/118391, WO2007/134298 andWO2006/117669; the entirety of each of which is hereby incorporated byreference. All these compounds, among others, can be labeled using knownchemistry in the art and be used in the provided methods describedherewith.

In some embodiments, a labeled compound of formula I has the structureof formula II,

wherein Y′ is —CH₂— or S;

X₄ is hydrogen or halogen; and R is an amino alkyl moiety, optionallysubstituted on the amino nitrogen with one or two carbon-containingsubstituents selected independently from the group consisting of alkyl,alkenyl and alkynyl substituents, wherein the total number of carbons inthe amino alkyl moiety is from 1 to 9.

In some embodiments, the labeled compound of formula I is an labeledanalog of compound A (PUH71):

wherein the labeled compound has at least one atom or substituentdetectable by a medical imaging technique.

In some embodiments, a labeled compound A is labeled at 2′-iodo. In someembodiments, a labeled compound A has ¹²³I at the 2′-iodo position. Insome embodiments, a labeled compound A has ¹²³I at the 2′-iodo positionand is used for SPECT imaging. In some embodiments, a labeled compound Ahas ¹²⁴I at the 2′-iodo position. In some embodiments, a labeledcompound A has ¹²⁴I at the 2′-iodo position and is used for PET imaging.

In some embodiments, a labeled compound of any of formula I to IX islabeled through substituting a hydrogen atom with a group that can bedetected by a medical imaging technique. In some embodiments, a labeledcompound of any of formula I to IX is labeled through substituting atleast one hydrogen atom in the compound with at least one group thatproduces higher signal intensity than the at least one hydrogen atom. Insome embodiments, a labeled compound of any of formula I to IX isradiolabeled. In some embodiments, a labeled compound comprises anisotope which decays by positron emission. In some embodiments, alabeled compound is labeled with one or more isotopes selected from¹²⁴I, ¹¹C, ¹⁵O, ¹³N, and ¹⁸F. In some embodiments, a labeled compound islabeled with ¹²⁴I. In some embodiments, a compound labeled with ¹²⁴I isused in PET imaging. In some embodiments, a compound labeled with ¹²³Iis used in SPECT imaging. In some embodiments, a labeled compoundcomprises an isotope that decays by electron capture. In someembodiments, a labeled compound comprises an isotope selected from ¹²³Iand ¹³¹I. In some embodiments, a labeled compound comprises one or morelabels suited for magnetic resonance imaging (MRI). In some embodiments,a labeled compound comprises one or more ¹⁹F. In some embodiments, acompound labeled with one or more ¹⁹F is used for MRI.

In some embodiments, a label is a fluorophore moiety. In someembodiments, a label is a nanometer-sized agent. In some embodiments, alabel is a nanoparticle. In some embodiments, a label is a nanotube. Insome embodiments, a label is liposome. In some embodiments, a nanotubeor liposome comprises a moiety that produces an enhanced signal. In someembodiments, one or more MRI agents are linked or packaged in ananotube, nanoparticle or liposome. In some embodiments, onenanometer-sized agent or nanoparticle or liposomal micelle is used tolabel more than one molecule a compound to be labeled; for example, morethan one molecule of the compound to be labeled can be linked to asingle nanoparticle. In some embodiments, a label is covalently linkedto a compound. In some embodiments, a label is non-covalently linked toa compound.

In some embodiments, a labeled compound is selected from

In some embodiments, a compound is labeled without changing theaffinity, selectivity or biodistribution profile of the inhibitor. Suchlabeled compounds are useful as probes for prognostic and/or diagnosticpurposes. In one embodiment, a labeled compound is an iodine 124radiolabeled version of an HSP90 inhibitor or a compound having thestructure of any of formula I to IX. In one embodiment, a labeledcompound is an iodine 123 radiolabeled version of an HSP90 inhibitor ora compound having the structure of any one of formula I to IX. In oneembodiment, a labeled compound is an iodine 131 radiolabeled version ofan HSP90 inhibitor or a compound having the structure of any one offormula I to IX. In one embodiment, a labeled compound is an iodine 125radiolabeled version of an HSP90 inhibitor or a compound having thestructure of any one of formula 1 to IX.

In another embodiment, a radiolabeled compound in a provided method isselected from a compound having the following formulae:

In some embodiments, a radiolabeled compound in a provided method isselected from a compound having the following formulae:

In some embodiments, a radiolabeled compound in a provided method isselected from a compound having the following formulae:

In some embodiments, a radiolabeled compound in a provided method isselected from a compound having the following formulae:

In some embodiments, a radiolabeled compound in a provided method isselected from a compound having the following formulae:

In some embodiments, a radiolabeled compound in a provided method isselected from a compound having the following formulae:

Methods of synthesizing the radiotracers in the above embodiments can befound for instance in U.S. Pat. No. 7,834,181, WO 2011/044394, WO2008/005937 and PCT application PCT/US2012/032371, the contents of eachof which are hereby incorporated by reference in their entirety.

EXEMPLIFICATION

Methods for preparing the labeled compounds are widely known in the art,for example but not limited to U.S. Pat. No. 7,834,181, the entirety ofwhich is hereby incorporated by reference. Suitable imagingtechnologies, such as PET, SPECT and CT, and their combination withother imaging and/or diagnostic techniques, are widely known andpracticed in the art as well.

Exemplary Procedure Using ¹²⁴I-PUH71 (Compound A with ¹²⁴I)

Positron emission tomography (PET) combined with X-ray computedtomography (CT) was performed using a state of the art integrated PET-CTscanner (Discovery DSTE™, General Electric). CT scans for attenuationcorrection and anatomic coregistration were performed prior totracer-injection, using the following acquisition parameters: 140 kVp;85 mA; pitch of 1.75:1; reconstructed slice thickness of 3.75 mm; 0.8 sper rotation. The CT protocol was designed for anatomic localization oftracer-signal and for attenuation correction, while minimizing radiationexposure. Each patient received ˜185 megabecquerel (MBq) [¹²⁴I]-PU-H71by peripheral vein over two minutes. PET emission scans were acquired intwo-dimensional mode starting at the mid-thighs moving toward the head,for 7.5 minutes per PET bed position. PET data were reconstructed usinga standard ordered subset expected maximization iterative algorithm.Emission data were corrected for scatter, attenuation and decay.Clinical FDG PET-CT studies were performed according to standard methodsusing state of the art PET-CT scanners. [¹²⁴I]-PU-H71 scans wereperformed at 3-4 hrs, 20-24 hrs, 48-72 hours and, optionally, 168 hrsafter tracer administration on the microdose [¹²⁴I]-PU-H71 PET-CT study.See FIGS. 1-2.

PU-PET images were taken 1.5, 4, 24 and 48-72 hrs afterco-administration on the tracer mixed with a therapeutic dose ofnon-radioactive PUH71 in a total volume of 100 Ml, co-infusedintravenously over one hour. Patient were treated with PU-H71 atescalating dose levels determined by a modified continuous reassessmentmodel. Each patient is treated with his or her assigned dose on day 1,4, 8 and 11 of each 21 day cycle. Pre- and post-treatment biopsies werecollected for correlative studies including LCMSMS quantification ofPU-H71, with the latter obtained within 24 hours of their cycle 1, day 1dose of PU-H71. See FIGS. 3-4.

Synthesis of [¹²⁴I]-PUH71

The general chemical scheme for the radiochemical synthesis of[¹²⁴I]-PU-H71 is illustrated below. [¹²⁴I]—NaI (˜50 μL) was transferredto 1 mL reacti-vial and to it trimethyl tin precursor (Me₃Sn-PU-H71) (25μg) dissolved in 20 μL of methanol was added. To the resulting solution15 μL of freshly prepared chloramine-T (1.5 mg/mL in acetic acid) wasadded and the reaction mixture was heated at 50° C. for 5 minutes. Thevial was allowed to cool for 2 min and 101 μL of methionine methyl ester(0.5 g/mL) in water was added. Finally, 10 μL of concentrated HCl wasadded and the solution was heated at 50° C. for 30 min with occasionalshaking. The reaction mixture was cooled to room temperature andpurified using HPLC. The product was collected and the solvent wasremoved under reduced pressure using a rotary evaporator. The finalproduct was formulated in 5% ethanol in saline (0.9%). 5% ethanol wasused to avoid adherence of the minute amounts of tracer to the walls ofthe flask. Next, the solution was passed through 0.22 μm filter intopyrogen free vial equipped with a sterile vent. A portion of finalformulation was withdrawn and used for quality control analysis.

What is claimed is:
 1. A method of imaging a tissue affected by aninflammation and/or infection in a subject in need thereof, comprisingsteps of: (a) administering to the subject a labeled compound that bindsto Hsp90; and (b) imaging the tissue by detecting the labeled compoundin the subject.
 2. A method of imaging a tissue affected by aninflammation and/or infection in a subject in need thereof, comprisingsteps of: (a) administering to the subject a labeled compound of any offormula I to IX as described in the specification; and (b) imaging thetissue by detecting the labeled compound in the subject.
 3. The methodof any one of the preceding claims, further comprising detecting thepresence of the inflammation and/or infection in the tissue by analyzingan image obtained in step (b).
 4. The method of any one of the precedingclaims, wherein the labeled compound is a labeled compound of formula I:

or its pharmaceutically acceptable salt thereof, wherein: each Y isindependently CH or N; R is hydrogen, a C₁ to C₁₀ alkyl, alkenyl,alkynyl, or an alkoxyalkyl group, optionally comprising one or moreheteroatoms, or a targeting moiety connected to N9 via a linker; X₄ ishydrogen or halogen; X₃ is CH₂, CF₂, S, SO, SO₂, O, NH, or NR², whereinR² is alkyl; X₂ is halogen, alkyl, alkoxy, halogenated alkoxy,hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino,dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino,alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl,C(O)O-alkyl, NH₂, OH, CN, SO₂X₅, NO₂, NO, C(S)R, NHSO₂X₅, or C(O)R,where X₅ is F, NH₂, alkyl, or H, and R₂ is alkyl, NH₂, NH-alkyl, orO-alkyl; and X₁ represents two substituents, which may be the same ordifferent, disposed in the 4′ and 5′ positions on the aryl group,wherein X₁ is selected from halogen, alkyl, alkoxy, halogenated alkoxy,hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino,dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino,alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl,NH₂OH, CN, SO₂X₅, NO₂, NO, C(S)R, NHSO₂X₅, or C(O)R, where X₅ is F, NH₂,alkyl, or H, and R₂ is alkyl, NH₂, NH-alkyl, or O-alkyl, C₁ to C₆ alkylor alkoxy, or wherein X₁ has the formula —O—(CH₂)—O—, wherein n is aninteger from 1 to 2, and one of the oxygens is bonded at the 5′-positionand the other at the 4′-position of the aryl ring wherein each hydrogenis optionally and independently substituted with a group that can bedetected by a medical imaging technique, and/or at least one atom in thecompound is optionally enriched in an isotope that can be detected by amedical imaging technique.
 5. The method of any one of the precedingclaims, wherein the labeled compound is labeled through substituting atleast one hydrogen atom in the compound with at least one group thatproduces higher signal intensity than the at least one hydrogen atom. 6.The method of any one of the preceding claims, wherein at least one atomin the labeled compound is enriched in an isotope that can be detectedby a medical imaging technique.
 7. The method of any one of thepreceding claims, wherein the labeled compound binds to one or moreisoforms of Hsp90.
 8. The method of any one of the preceding claims,wherein the labeled compound binds to a stress-specific form of Hsp90.9. The method of any one of the preceding claims, wherein the labeledcompound binds to a stress-specific form of Hsp90 selectively over ahousekeeping form of Hsp90.
 10. The method of claim 9, wherein a ratioof binding stress-specific Hsp90 to a housekeeping form of Hsp90 ofabout 1.5 or greater indicates that an inflammation/infection subjectwill be susceptible to Hsp90 inhibition therapy.
 11. The method of anyone of the preceding claims, wherein the labeled compound has a K_(D) ofless than about 1 mM, about 100 μM, about 10 μM, or about 1 μM.
 12. Themethod of any one of the preceding claims, wherein the labeled compoundinhibits Hsp90.
 13. The method of claim 12, wherein the labeled compoundhas an IC₅₀ of less than about 1 mM, about 100 μM, about 10 μM, or about1 μM.
 14. The method of any one of the preceding claims, wherein theimaging process comprises tomography.
 15. The method of claim 14,wherein the imaging process comprises positron emission tomography(PET).
 16. The method of claim 15, wherein PET is combined with anotherimaging technique.
 17. The method of claim 15, wherein PET is combinedwith X-ray Computed Tomography (CT), Magnetic Resonance Imaging (MRT),or single-photon emission computed tomography (SPECT).
 18. The method ofclaim 14, wherein the imaging process comprises single-photon emissioncomputed tomography (SPECT).
 19. The method of any one of the precedingclaims, further comprising collecting electrocardiography (ECG) data.20. The method of claim 19, wherein ECG data are collected prior to,concurrent with, and/or subsequent to the imaging process.
 21. Themethod of claim 20, comprising collecting ECG data during the imagingprocess.
 22. The method of any one of the preceding claims, wherein thestep of imaging comprises imaging by multiple modalities.
 23. The methodof any one of the preceding claims, wherein detecting the labeledcompound in the subject comprises measuring signal intensity from thelung of the subject.
 24. The method of any one of the preceding claims,wherein detecting the labeled compound in the subject comprisesmeasuring signal intensity from the colon of the subject.
 25. The methodof any one of the preceding claims, wherein detecting the labeledcompound in the subject comprises measuring signal intensity from theskin of the subject.
 26. The method of any one of the preceding claims,wherein detecting the labeled compound in the subject comprisesmeasuring signal intensity from the macrophages of the subject.
 27. Themethod of any one of the preceding claims, wherein detecting the labeledcompound in the subject comprises measuring signal intensity from thestroma of the subject.
 28. The method of any one of the precedingclaims, wherein detecting the labeled compound in the subject comprisesmeasuring signal intensity from the cardiac tissue of the subject. 29.The method of any one of the preceding claims, wherein the inflammationand/or infection is associated with Hsp90.
 30. The method of any one ofthe preceding claims, wherein the inflammation and/or infection isassociated with stress-specific Hsp90.
 31. The method of any one of thepreceding claims, wherein the labeled compound is administered before,during, or after administration of a non-radioactive therapeuticcompound.
 32. The method of any one of the preceding claims, wherein thelabeled compound has a physical half-life of at least about 0.1, 0.2,0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 36, 48, 72, 96, or100.3 hours.
 33. The method of any one of the preceding claims, whereinthe imaging measures the accessibility of Hsp90 in the tissue affectedby the inflammation and/or infection to a therapeutic compound.
 34. Themethod of any one of the preceding claims, wherein the imaging measuresthe concentrations of a labeled and/or non-labeled therapeutic compoundin the tissue affected by the inflammation and/or infection.
 35. Themethod of claim 34, wherein the imaging measures the concentration ofnon-labeled therapeutic compound by use of a radiotracer amount oflabeled compound.
 36. The method of claim 34, wherein the imagingmeasures tissue concentrations of radioactivity for labeled-compoundadministered at a therapeutically effective amount.
 37. The method ofany one of the preceding claims, wherein the imaging measures theoccupancy or saturation of Hsp90 by a therapeutic compound in the tissueaffected by the inflammation and/or infection, or the ability of atherapeutic compound to displace the labeled compound in the tissueaffected by the inflammation and/or infection.
 38. A method for thetreatment of a tissue affected by, or prevention of an tissue from, aninflammation and/or infection, comprising steps of (a) administering alabeled compound of any of formula I to IX to a subject in need thereof,and (b) imaging the tissue by detecting the labeled compound in thesubject.
 39. A method for the treatment of a tissue affected by, orprevention of an tissue from, an inflammation and/or infection,comprising the step of administering a labeled compound of any offormula I to IX to a subject in need thereof.
 40. A method for thetreatment of a tissue affected by, or prevention of an tissue from, aninflammation and/or infection, comprising the step of administering anon-radioactive therapeutic compound of formula X.
 41. A method formonitoring the effect of an inflammation and/or infection treatment in asubject in need thereof, comprising steps of: (a) administering alabeled compound of any of formula I to IX to the subject who isscheduled for the inflammation and/or infection treatment, currentlyundergoing the inflammation and/or infection treatment, or has completedor discontinued the inflammation and/or infection treatment; (b) imaginga tissue affected by the inflammation and/or infection by detecting thelabeled compound; and (c) recommending to the subject an appropriateavoidance, continuation, modification, or termination in theinflammation and/or infection treatment.
 42. A method for monitoring aninflammation and/or infection treatment regimen, comprising steps of:(a) administering a labeled compound of any of formula I to IX to asubject under the inflammation and/or infection treatment regimen; (b)imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound in the subject; (c) analyzing the imagesfrom step (b); and (d) maintaining, modifying, or discontinuing theinflammation and/or infection treatment regimen.
 43. A method forselecting subjects for an inflammation and/or infection treatment,comprising steps of: (a) administering a labeled compound of any offormula I to IX to a subject; (b) imaging a tissue affected by theinflammation and/or infection by detecting the labeled compound in thesubject; (c) analyzing the images from step (b); and (d) including orexcluding the subject for the treatment.
 44. A method for selectingsubjects for an inflammation and/or infection treatment, comprisingsteps of: (a) administering to a subject a labeled compound that bindsto stress-specific Hsp90; and (b) imaging a tissue affected by theinflammation and/or infection by detecting the labeled compound in thesubject; wherein increased uptake of the labeled compound indicates morelikelihood for the subject to benefit from the treatment.
 45. The methodof claim 44, wherein the treatment comprises the use of a compound thatbinds to Hsp90.
 46. The method of claim 45, wherein the treatmentcomprises the use of a compound that binds to stress-specific Hsp90. 47.The method of any one of claims 38, 39, or 41-44, wherein the treatmentcomprises the use of the non-labeled counterpart of the labeledcompound.
 48. The method of claim 47, wherein the non-labeledcounterpart is of formula X.
 49. The method of claim 47, wherein thenon-labeled counterpart is compound A:


50. The method of any one of claims 40 or 47-49, where the methodfurther comprises a standard of care treatment of the inflammation orinfection.
 51. The method of any one of claims 47-49, wherein the methodfurther comprises co-administration of anti-inflammatory agents,antihistamines, immunosuppressive agents, anti-viral agents, anti-fungalagents, antibacterial agents, anti-parasitic agents, or a combinationthereof.
 52. A method for determining the dosage of a drug for thetreatment of an inflammation and/or infection, comprising steps of: (a)administering a labeled compound of any of formula I to IX to a subject;(b) imaging a tissue affected by the inflammation and/or infection bydetecting the labeled compound in the subject; (c) analyzing the imagesfrom step (b); and (d) administering to the subject a suitable amount ofthe drug.
 53. The method of claim 52, further comprising administering anon-radioactive therapeutic amount of a compound that binds to Hsp90.54. The method of claim 53, wherein analyzing the images in step (c) isdone with comparison to images obtained when administering only thelabeled compound.
 55. The method of claim 52 or 53, wherein the labeledcompound is administered before, during, or after administration of anon-radioactive therapeutic compound.
 56. The method of claim 52,wherein the drug is a therapeutic compound that binds to Hsp90.
 57. Themethod of any one of the preceding claims, wherein the labeled compoundis a labeled compound having the structure of: wherein Y′ is —CH₂— or S;X₄ is hydrogen or halogen; and R is an amino alkyl moiety, optionallysubstituted on the amino nitrogen with one or two carbon-containingsubstituents selected independently from the group consisting of alkyl,alkenyl and alkynyl substituents, wherein the total number of carbons inthe amino alkyl moiety is from 1 to
 9. 58. The method of any one of thepreceding claims, wherein the labeled compound is labeled compound A:


59. The method of claim 58, wherein compound A is labeled at 2′-iodo.


60. The method of claim 58, wherein compound A is labeled throughsubstituting a hydrogen atom with a group that can be detected by amedical imaging technique.
 61. The method of any one of the precedingclaims, wherein the labeled compound is radiolabelled.
 62. The method ofany one of the preceding claims, wherein the labeled compound comprisesan isotope which decays by positron emission.
 63. The method of any oneof the preceding claims, wherein the labeled compound comprises anisotope selected from ¹²⁴I, ¹¹C, ¹⁵O, ¹³N, and ¹⁸F.
 64. The method ofany one of the preceding claims, wherein the labeled compound comprises¹²⁴I.
 65. The method of any one of the preceding claims, wherein thelabeled compound comprises an isotope that decays by electron capture.66. The method of any one of the preceding claims, wherein the labeledcompound comprises an isotope selected from ¹²³I and ¹³¹I.
 67. Themethod of any one of the preceding claims, wherein the labeled compoundcomprises one or more ¹⁹F.
 68. The method of any one of the precedingclaims, wherein the labeled compound comprises a nanotube containingcontrast reagents for MRI.
 69. The method of any one of claims 1-56,wherein the labeled compound is selected from:


70. The method of claim 31, wherein the non-radioactive therapeuticcompound has the structure of formula X:

or its pharmaceutically acceptable salt thereof, wherein: each Y isindependently CH or N; R is hydrogen, a C₁ to C₁₀ alkyl, alkenyl,alkynyl, or an alkoxyalkyl group, optionally comprising one or moreheteroatoms, or a targeting moiety connected to N9 via a linker; X₄ ishydrogen or halogen; X₃ is CH₂, CF₂, s, SO, SO₂, O, NH, or NR², whereinR² is alkyl; X₂ is halogen, alkyl, alkoxy, halogenated alkoxy,hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino,dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino,alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl,C(O)O-alkyl, NH₂, OH, CN, SO₂X₅, NO₂, NO, C(S)R, NHSO₂X₅, or C(O)R,where X₅ is F, NH₂, alkyl, or H, and R₂ is alkyl, NH₂, NH-alkyl, orO-alkyl; and X₁ represents two substituents, which may be the same ordifferent, disposed in the 4′ and 5′ positions on the aryl group,wherein X₁ is selected from halogen, alkyl, alkoxy, halogenated alkoxy,hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino,dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino,alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl,NH₂OH, CN, SO₂X₅, NO₂, NO, C(S)R, NHSO₂X₅, or C(O)R, where X₅ is F, NH₂,alkyl, or H, and R₂ is alkyl, NH₂, NH-alkyl, or O-alkyl, C₁ to C₆ alkylor alkoxy, or wherein X₁ has the formula —O—(CH₂)—O—, wherein n is aninteger from 1 to 2, and one of the oxygens is bonded at the 5′-positionand the other at the 4′-position of the aryl ring; or thenon-radioactive therapeutic compound is a non-radioactive counterpart ofa compound having the structure of any of formula III to IX.
 71. Themethod of claim 70, wherein the non-radioactive therapeutic compound is


72. The method of any of the preceding claims, wherein the imaging isnon-invasive.
 73. The method of any one of the preceding claims, furthercomprising identifying abnormal signal compared to a reference, whereinthe abnormal signal indicates an inflammation and/or infection in thetissue.
 74. The method of any one of the preceding claims, furthercomprising identifying decreased signal compared to a reference, whereinthe decreased signal indicates amelioration of an inflammation and/orinfection in the tissue.
 75. The method of any one of the precedingclaims, wherein the subject is a cancer patient.